Journal articles on the topic 'Connective Tissue Growth Factor ECM'
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1
Effendi, Wiwin Is, and Tatsuya Nagano. "Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge." International Journal of Molecular Sciences 23, no. 11 (May 28, 2022): 6064. http://dx.doi.org/10.3390/ijms23116064.
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CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.
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Ramirez, Francesco, Lynn Y. Sakai, Harry C. Dietz, and Daniel B. Rifkin. "Fibrillin microfibrils: multipurpose extracellular networks in organismal physiology." Physiological Genomics 19, no. 2 (October 4, 2004): 151–54. http://dx.doi.org/10.1152/physiolgenomics.00092.2004.
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Organismal physiology depends significantly on the proper assembly of extracellular matrix (ECM) macroaggregates that impart structural integrity to the connective tissue. Recent genetic studies in mice have unraveled unsuspected new functions of architectural matrix components in regulating signaling events that modulate patterning, morphogenesis, and growth of several organ systems. As a result, a new paradigm has emerged whereby tissue-specific organization of the ECM dictates not only the physical properties of the connective tissue, but also the ability of the matrix to direct a broad spectrum of cellular activities through the regulation of growth factor signaling. These observations pave the way to novel therapeutic approaches aimed at counteracting the deleterious consequences of perturbations of connective tissue homeostasis.
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Albeiroti, Sami, Artin Soroosh, and Carol A. de la Motte. "Hyaluronan’s Role in Fibrosis: A Pathogenic Factor or a Passive Player?" BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/790203.
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Fibrosis is a debilitating condition that can lead to impairment of the affected organ’s function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor-β(TGF-β) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF-βand whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases.
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Harlow, Christopher R., Angela C. Bradshaw, Michael T. Rae, Kirsty D. Shearer, and Stephen G. Hillier. "Oestrogen formation and connective tissue growth factor expression in rat granulosa cells." Journal of Endocrinology 192, no. 1 (January 2007): 41–52. http://dx.doi.org/10.1677/joe.1.06689.
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Ovarian follicular development involves continual remodelling of the extracellular matrix (ECM) forming the basement membrane and intercellular framework that support granulosa cell (GC) growth and differentiation. Insight into the molecular regulation of ovarian ECM remodelling is potentially translatable to tissue remodelling elsewhere in the body. We therefore studied the link between a gene marker of ECM remodelling (connective tissue growth factor (CTGF)) and oestrogen biosynthesis (cytochrome P450aromatase (P450arom)) in rat granulosa cells. To determine if a cause–effect interaction exists, we used semi-quantitative in situ hybridisation to analyse patterns of CTGF and P450arom mRNA expression and immunohistochemistry to detect CTGF protein localisation throughout follicular development, and tested the actions of CTGF on oestrogen biosynthesis and oestradiol on CTGF mRNA expression in isolated GC in vitro. CTGF mRNA levels in GC rose gradually through small preantral (SP) and small antral (SA) stages of development to a maximum (fivefold higher) in large antral (LA) follicles. In preovulatory (PO) follicles, the CTGF mRNA level fell to 30% of that in SP follicles. P450arom mRNA also increased (threefold in LA relative to SP) throughout antral development follicles, but in contrast to CTGF continued to increase (12-fold) in PO follicles. In the cumulus oophorus of PO follicles, the residual GC CTGF mRNA expression increased with proximity to the oocyte, being inversely related to P450arom. Elsewhere in the follicle wall, there was a mural-to-antral gradient of CTGF mRNA expression, again inversely related to P450arom. Immunohistochemistry showed CTGF protein localisation broadly followed mRNA expression during follicular development, although the protein was also present in the theca interna and ovarian surface epithelium. Gradients in CTGF expression across the cumulus oophorus and follicle wall were similar to those observed for mRNA with CTGF protein expression being greatest in proximity to the oocyte. Treatment of isolated GC from preantral and SA follicles with recombinant human CTGF (1–100 ng/ml) did not affect basal or FSH-stimulated GC aromatase activity. However, in the absence of FSH, oestradiol (10−7–10−5 M) stimulated CTGF mRNA expression up to twofold. Conversely, FSH (10 ng/ml) alone reduced CTGF mRNA expression by 40% and combined treatment with FSH and oestradiol further suppressed CTGF to 10% of the control value. The oestrogen receptor (ER) antagonist, ICI 182 780 blocked the stimulatory and inhibitory effects of oestradiol, suggesting a specific ER-mediated mode of action on CTGF. Therefore, CTGF gene expression in GC is under local control by oestrogen whose effect (positive or negative) is modulated by FSH. This helps explain why gene expression of CTGF and P450arom diverge in FSH-induced PO follicles and has implications for oestrogenic regulation of CTGF formation elsewhere in the body.
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Silver, Frederick H., Dale DeVore, and Lorraine M. Siperko. "Invited Review: Role of mechanophysiology in aging of ECM: effects of changes in mechanochemical transduction." Journal of Applied Physiology 95, no. 5 (November 2003): 2134–41. http://dx.doi.org/10.1152/japplphysiol.00429.2003.
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Mechanical forces play a role in the development and evolution of extracellular matrices (ECMs) found in connective tissue. Gravitational forces acting on mammalian tissues increase the net muscle forces required for movement of vertebrates. As body mass increases during development, musculoskeletal tissues and other ECMs are able to adapt their size to meet the increased mechanical requirements. However, the control mechanisms that allow for rapid growth in tissue size during development are altered during maturation and aging. The purpose of this mini-review is to examine the relationship between mechanical loading and cellular events that are associated with downregulation of mechanochemical transduction, which appears to contribute to aging of connective tissue. These changes result from decreases in growth factor and hormone levels, as well as decreased activation of the phosphorelay system that controls cell division, gene expression, and protein synthesis. Studies pertaining to the interactions among mechanical forces, growth factors, hormones, and their receptors will better define the relationship between mechanochemical transduction processes and cellular behavior in aging tissues.
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Chang, Patrick C., Janine M. Low-Marchelli, Ashkan Shahbandi, Daniel J. Goff, and Catriona Jamieson. "Connective Tissue Growth Factor Induces Anti-Apoptotic Factors in Chronic Myeloid Leukemia Stem Cells." Blood 124, no. 21 (December 6, 2014): 1785. http://dx.doi.org/10.1182/blood.v124.21.1785.1785.
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Abstract Chronic Myeloid Leukemia (CML) is a progressive hematopoietic malignancy where expression of the oncogenic fusion protein BCR-ABL1 in leukemia stem cells (LSCs) prevents the proper differentiation of myeloid progenitor populations, leading to accumulation of undifferentiated blasts. Current treatments target BCR-ABL1 with tyrosine kinase inhibitors (TKIs). Though effective if administered continuously, TKIs generally fail to eradicate the bone marrow niche-residing LSCs responsible for patient relapse or progression of CML to its terminal stage, Blast Crisis (BC), as evidenced by the high molecular relapse rate following TKI discontinuation. Previous studies performed by ourselves and others show that BC progenitors (CD34+CD38+Lin-) exhibit stem-like behaviors, such as quiescence, self-renewal, and induction of pro-survival gene expression through alternative splicing of BCL2 family members, and thus behave like LSCs. Notably, BC CML LSCs co-cultured on LSC (SL/M2) supportive stroma are resistant to TKIs compared to culturing the cells alone, indicating a role of the extracellular matrix (ECM) in promoting LSC survival. We performed RNA-seq and qRT-PCR of CD34+CD38+Lin- progenitor cells in CML patient samples and found a significant increase in CTGF (Connective Tissue Growth Factor) expression in BC CML versus chronic phase (CP). Interestingly, CTGF is an ECM protein that enhances cell adhesion and has been shown to predict therapeutic resistance in cancers, such as acute lymphoblastic leukemia (ALL). Lentiviral overexpression of CTGF in a CML cell line K562 and CD34+ CP CML patient samples caused proliferation and a decrease in apoptosis markers (cleaved caspase-3), as measured by FACS analysis. Moreover, qRT-PCR analysis of mRNA indicated an increase in pro-survival BCL2 family gene expression. These changes were not observed in normal CD34+ cord blood cells. Currently, lentiviral CTGF transduction of CP CML followed by transplantation into RAG2-/-gc-/- and NSG-S mice will be used to determine the effects of CTGF on LSC maintenance in vivo. In conclusion, CTGF promotes CML LSC survival in vitro and thus could be a key factor in BC transformation and TKI resistance. Disclosures Jamieson: J&J, Roche: Research Funding.
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Miyashita, Naoya, and Akira Saito. "Organ Specificity and Heterogeneity of Cancer-Associated Fibroblasts in Colorectal Cancer." International Journal of Molecular Sciences 22, no. 20 (October 11, 2021): 10973. http://dx.doi.org/10.3390/ijms222010973.
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Fibroblasts constitute a ubiquitous mesenchymal cell type and produce the extracellular matrix (ECM) of connective tissue, thereby providing the structural basis of various organs. Fibroblasts display differential transcriptional patterns unique to the organ of their origin and they can be activated by common stimuli such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) signaling. Cancer-associated fibroblasts (CAFs) reside in the cancer tissue and contribute to cancer progression by influencing cancer cell growth, invasion, angiogenesis and tumor immunity. CAFs impact on the tumor microenvironment by remodeling the ECM and secreting soluble factors such as chemokines and growth factors. Differential expression patterns of molecular markers suggest heterogeneous features of CAFs in terms of their function, pathogenic role and cellular origin. Recent studies elucidated the bimodal action of CAFs on cancer progression and suggest a subgroup of CAFs with tumor-suppressive effects. This review attempts to describe cellular features of colorectal CAFs with an emphasis on their heterogeneity and functional diversity.
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Vogelmann, R., D. Ruf, M. Wagner, G. Adler, and A. Menke. "Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-β1 transgenic mouse model." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 1 (January 1, 2001): G164—G172. http://dx.doi.org/10.1152/ajpgi.2001.280.1.g164.
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The pancreas morphology of transgenic mice that overexpress transforming growth factor-β1 (TGF-β1) in the pancreas resembles partially morphological features of chronic pancreatitis, such as progressive accumulation of extracellular matrix (ECM). Using this transgenic mouse model, we characterized the composition of pancreatic fibrosis and involved fibrogenic mediators. On day 14 after birth, fibrotic tissue was mainly composed of collagen type I and III. At this time, mRNA levels of TGF-β1 were increased. On day 70, the ECM composition was expanded by increased deposition of fibronectin, whereas connective tissue growth factor, fibroblast growth factor (FGF)-1, and FGF-2 mRNA expression levels were elevated in addition to TGF-β1. In parallel, the number of pancreatic stellate cells (PSC) increased over time. In vitro, TGF-β1 stimulated collagen type I expression but not fibronectin expression in PSC, in contrast to FGF-2, which stimulated both. This confirms that TGF-β1 mediates pancreatic fibrosis through activation of PSC and deposition of collagen type I and III at early time points. Furthermore, this points to an indirect mechanism in which TGF-β regulates pancreatic ECM assembly by induction of additional growth factors.
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Ritelli, Marco, Nicola Chiarelli, Valeria Cinquina, Nicoletta Zoppi, Valeria Bertini, Marina Venturini, and Marina Colombi. "RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms." Cells 11, no. 24 (December 14, 2022): 4040. http://dx.doi.org/10.3390/cells11244040.
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Hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are clinically overlapping connective tissue disorders of unknown etiology and without any validated diagnostic biomarker and specific therapies. Herein, we in-depth characterized the cellular phenotype and gene expression profile of hEDS and HSD dermal fibroblasts by immunofluorescence, amplicon-based RNA-seq, and qPCR. We demonstrated that both cell types show a common cellular trait, i.e., generalized extracellular matrix (ECM) disarray, myofibroblast differentiation, and dysregulated gene expression. Functional enrichment and pathway analyses clustered gene expression changes in different biological networks that are likely relevant for the disease pathophysiology. Specifically, the complex gene expression dysregulation (mainly involving growth factors, structural ECM components, ECM-modifying enzymes, cytoskeletal proteins, and different signal transducers), is expected to perturb many ECM-related processes including cell adhesion, migration, proliferation, and differentiation. Based on these findings, we propose a disease model in which an unbalanced ECM remodeling triggers a vicious cycle with a synergistic contribution of ECM degradation products and proinflammatory mediators leading to a functional impairment of different connective tissues reflecting the multisystemic presentation of hEDS/HSD patients. Our results offer many promising clues for translational research aimed to define molecular bases, diagnostic biomarkers, and specific therapies for these challenging connective tissue disorders.
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Pouw, Andrew E., Mark A. Greiner, Razek G. Coussa, Chunhua Jiao, Ian C. Han, Jessica M. Skeie, John H. Fingert, Robert F. Mullins, and Elliott H. Sohn. "Cell–Matrix Interactions in the Eye: From Cornea to Choroid." Cells 10, no. 3 (March 20, 2021): 687. http://dx.doi.org/10.3390/cells10030687.
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The extracellular matrix (ECM) plays a crucial role in all parts of the eye, from maintaining clarity and hydration of the cornea and vitreous to regulating angiogenesis, intraocular pressure maintenance, and vascular signaling. This review focuses on the interactions of the ECM for homeostasis of normal physiologic functions of the cornea, vitreous, retina, retinal pigment epithelium, Bruch’s membrane, and choroid as well as trabecular meshwork, optic nerve, conjunctiva and tenon’s layer as it relates to glaucoma. A variety of pathways and key factors related to ECM in the eye are discussed, including but not limited to those related to transforming growth factor-β, vascular endothelial growth factor, basic-fibroblastic growth factor, connective tissue growth factor, matrix metalloproteinases (including MMP-2 and MMP-9, and MMP-14), collagen IV, fibronectin, elastin, canonical signaling, integrins, and endothelial morphogenesis consistent of cellular activation-tubulogenesis and cellular differentiation-stabilization. Alterations contributing to disease states such as wound healing, diabetes-related complications, Fuchs endothelial corneal dystrophy, angiogenesis, fibrosis, age-related macular degeneration, retinal detachment, and posteriorly inserted vitreous base are also reviewed.
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Gore-Hyer, Elizabeth, Daniel Shegogue, Malgorzata Markiewicz, Shianlen Lo, Debra Hazen-Martin, Eddie L. Greene, Gary Grotendorst, and Maria Trojanowska. "TGF-β and CTGF have overlapping and distinct fibrogenic effects on human renal cells." American Journal of Physiology-Renal Physiology 283, no. 4 (October 1, 2002): F707—F716. http://dx.doi.org/10.1152/ajprenal.00007.2002.
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Transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) are ubiquitously expressed in various forms of tissue fibrosis, including fibrotic diseases of the kidney. To clarify the common and divergent roles of these growth factors in the cells responsible for pathological extracellular matrix (ECM) deposition in renal fibrosis, the effects of TGF-β and CTGF on ECM expression in primary human mesangial (HMCs) and human proximal tubule epithelial cells (HTECs) were studied. Both TGF-β and CTGF significantly induced collagen protein expression with similar potency in HMCs. Additionally, α2(I)-collagen promoter activity and mRNA levels were similarly induced by TGF-β and CTGF in HMCs. However, only TGF-β stimulated collagenous protein synthesis in HTECs. HTEC expression of tenascin-C (TN-C) was increased by TGF-β and CTGF, although TGF-β was the more potent inducer. Thus both growth factors elicit similar profibrogenic effects on ECM production in HMCs, while promoting divergent effects in HTECs. CTGF induction of TN-C, a marker of epithelial-mesenchymal transdifferentiation (EMT), with no significant induction of collagenous protein synthesis in HTECs, may suggest a more predominant role for CTGF in EMT rather than induction of excessive collagen deposition by HTECs during renal fibrosis.
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Rayego-Mateos, Sandra, Sofia Campillo, Raúl R. Rodrigues-Diez, Antonio Tejera-Muñoz, Laura Marquez-Exposito, Roel Goldschmeding, Diego Rodríguez-Puyol, Laura Calleros, and Marta Ruiz-Ortega. "Interplay between extracellular matrix components and cellular and molecular mechanisms in kidney fibrosis." Clinical Science 135, no. 16 (August 2021): 1999–2029. http://dx.doi.org/10.1042/cs20201016.
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Abstract Chronic kidney disease (CKD) is characterized by pathological accumulation of extracellular matrix (ECM) proteins in renal structures. Tubulointerstitial fibrosis is observed in glomerular diseases as well as in the regeneration failure of acute kidney injury (AKI). Therefore, finding antifibrotic therapies comprises an intensive research field in Nephrology. Nowadays, ECM is not only considered as a cellular scaffold, but also exerts important cellular functions. In this review, we describe the cellular and molecular mechanisms involved in kidney fibrosis, paying particular attention to ECM components, profibrotic factors and cell–matrix interactions. In response to kidney damage, activation of glomerular and/or tubular cells may induce aberrant phenotypes characterized by overproduction of proinflammatory and profibrotic factors, and thus contribute to CKD progression. Among ECM components, matricellular proteins can regulate cell–ECM interactions, as well as cellular phenotype changes. Regarding kidney fibrosis, one of the most studied matricellular proteins is cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), currently considered as a fibrotic marker and a potential therapeutic target. Integrins connect the ECM proteins to the actin cytoskeleton and several downstream signaling pathways that enable cells to respond to external stimuli in a coordinated manner and maintain optimal tissue stiffness. In kidney fibrosis, there is an increase in ECM deposition, lower ECM degradation and ECM proteins cross-linking, leading to an alteration in the tissue mechanical properties and their responses to injurious stimuli. A better understanding of these complex cellular and molecular events could help us to improve the antifibrotic therapies for CKD.
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Zheng, Shizhong, and Anping Chen. "Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 5 (May 2006): G883—G893. http://dx.doi.org/10.1152/ajpgi.00450.2005.
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Upon liver injury, quiescent hepatic stellate cells (HSCs), the most relevant cell type for hepatic fibrogenesis, become active and overproduce extracellular matrix (ECM). Connective tissue growth factor (CTGF) promotes ECM production. Overexpression of CTGF during hepatic fibrogenesis is induced by transforming growth factor (TGF)-β. We recently demonstrated that curcumin reduced cell growth and inhibited ECM gene expression in activated HSCs. Curcumin induced gene expression of peroxisome proliferator-activated receptor (PPAR)-γ and stimulated its activity in activated HSCs, which was required for curcumin to suppress ECM gene expression, including αI(I)-collagen. The underlying mechanisms remain largely unknown. The aim of this study was to elucidate the mechanisms by which curcumin suppresses αI(I)-collagen gene expression in activated HSCs. We hypothesize that inhibition of αI(I)-collagen gene expression in HSCs by curcumin is mediated by suppressing CTGF gene expression through attenuating oxidative stress and interrupting TGF-β signaling. The present report demonstrated that curcumin significantly reduced the abundance of CTGF in passaged HSCs and suppressed its gene expression. Exogenous CTGF dose dependently abrogated the inhibitory effect of curcumin. Activation of PPAR-γ by curcumin resulted in the interruption of TGF-β signaling by suppressing gene expression of TGF-β receptors, leading to inhibition of CTGF gene expression. The phytochemical showed its potent antioxidant property by significantly increasing the level of total glutathione (GSH) and the ratio of GSH to GSSG in activated HSCs. De novo synthesis of cellular GSH was a prerequisite for curcumin to interrupt TGF-β signaling and inhibited gene expression of CTGF and αI(I)-collagen in activated HSCs. Taken together, our results demonstrate that inhibition of αI(I)-collagen gene expression by curcumin in activated HSCs results from suppression of CTGF gene expression through increasing cellular GSH contents and interruption of TGF-β signaling. These results provide novel insights into the mechanisms underlying inhibition of HSC activation by curcumin.
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KJÆR, MICHAEL. "Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading." Physiological Reviews 84, no. 2 (April 2004): 649–98. http://dx.doi.org/10.1152/physrev.00031.2003.
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Kjær, Michael. Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading. Physiol Rev 84: 649–698, 2004; 10.1152/physrev.00031.2003.—The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.
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Yamaguchi, Yoko, Akira Saito, Masafumi Horie, Akira Aoki, Patrick Micke, Mitsuhiro Ohshima, and Kai Kappert. "Targeting hepatocyte growth factor in epithelial–stromal interactions in an in vitro experimental model of human periodontitis." Odontology 109, no. 4 (June 14, 2021): 912–20. http://dx.doi.org/10.1007/s10266-021-00625-0.
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AbstractPeriodontitis is a chronic inflammatory disease leading to progressive connective tissue degradation and loss of the tooth-supporting bone. Clinical and experimental studies suggest that hepatocyte growth factor (HGF) is involved in the dysregulated fibroblast–epithelial cell interactions in periodontitis. The aim of this study was to explore effects of HGF to impact fibroblast-induced collagen degradation. A patient-derived experimental cell culture model of periodontitis was applied. Primary human epithelial cells and fibroblasts isolated from periodontitis-affected gingiva were co-cultured in a three-dimensional collagen gel. The effects of HGF neutralizing antibody on collagen gel degradation were tested and transcriptome analyses were performed. HGF neutralizing antibody attenuated collagen degradation and elicited expression changes of genes related to extracellular matrix (ECM) and cell adhesion, indicating that HGF signaling inhibition leads to extensive impact on cell–cell and cell–ECM interactions. Our study highlights a potential role of HGF in periodontitis. Antagonizing HGF signaling by a neutralizing antibody may represent a novel approach for periodontitis treatment.
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Blokland, Kaj E. C., Habibie Habibie, Theo Borghuis, Greta J. Teitsma, Michael Schuliga, Barbro N. Melgert, Darryl A. Knight, Corry-Anke Brandsma, Simon D. Pouwels, and Janette K. Burgess. "Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM." Cells 10, no. 7 (June 29, 2021): 1628. http://dx.doi.org/10.3390/cells10071628.
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Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16Ink4a and p21Waf1/Cip1. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.
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Chang, Hsun-Ming, Jung-Chien Cheng, Yingtao Liu, Christian Klausen, Congjian Xu, and Peter C. K. Leung. "Activin A-induced increase in LOX activity in human granulosa–lutein cells is mediated by CTGF." Reproduction 152, no. 4 (October 2016): 293–301. http://dx.doi.org/10.1530/rep-16-0254.
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Lysyl oxidase (LOX) is the key enzyme involved in the crosslinking of collagen and elastin that is essential for the formation of extracellular matrix (ECM). LOX-mediated ECM remodeling plays a critical role in follicle development, oocyte maturation and corpus luteum formation. To date, the regulation of LOX in human ovary has never been elucidated. Activin A and its functional receptors are highly expressed in ovarian follicles from an early developmental stage. They locally regulate follicle progression. The aim of this study was to investigate the effects of activin A on the expression of LOX and its extracellular enzyme activity in primary and immortalized human granulosa–lutein cells obtained from patients undergoing anin vitrofertilization procedure. We demonstrated that activin A significantly upregulated the expression of connective tissue growth factor (CTGF) and LOX via an activin/TGF-β type I receptor mediated-signaling pathway. Using a target depletion small interfering RNA knockdown approach, we further confirmed that the upregulation of CTGF expression resulted in an activin-A-induced increases in LOX expression and activity. These findings may provide insight into the mechanisms by which intrafollicular growth factors regulate the expression of LOX for ECM formation and tissue remodeling in the human ovary.
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Chaqour, Brahim, and Charles Karrasch. "Eyeing the Extracellular Matrix in Vascular Development and Microvascular Diseases and Bridging the Divide between Vascular Mechanics and Function." International Journal of Molecular Sciences 21, no. 10 (May 15, 2020): 3487. http://dx.doi.org/10.3390/ijms21103487.
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The extracellular matrix (ECM) is critical in all aspects of vascular development and health: supporting cell anchorage, providing structure, organization and mechanical stability, and serving as a sink for growth factors and sustained survival signals. Abnormal changes in ECM protein expression, organization, and/or properties, and the ensuing changes in vascular compliance affect vasodilator responses, microvascular pressure transmission, and collateral perfusion. The changes in microvascular compliance are independent factors initiating, driving, and/or exacerbating a plethora of microvascular diseases of the eye including diabetic retinopathy (DR) and vitreoretinopathy, retinopathy of prematurity (ROP), wet age-related macular degeneration (AMD), and neovascular glaucoma. Congruently, one of the major challenges with most vascular regenerative therapies utilizing localized growth factor, endothelial progenitor, or genetically engineered cell delivery, is the regeneration of blood vessels with physiological compliance properties. Interestingly, vascular cells sense physical forces, including the stiffness of their ECM, through mechanosensitive integrins, their associated proteins and the actomyosin cytoskeleton, which generates biochemical signals that culminate in a rapid expression of matricellular proteins such as cellular communication network 1 (CCN1) and CCN2 (aka connective tissue growth factor or CTGF). Loss or gain of function of these proteins alters genetic programs of cell growth, ECM biosynthesis, and intercellular signaling, that culminate in changes in cell behavior, polarization, and barrier function. In particular, the function of the matricellular protein CCN2/CTGF is critical during retinal vessel development and regeneration wherein new blood vessels form and invest a preformed avascular neural retina following putative gradients of matrix stiffness. These observations underscore the need for further in-depth characterization of the ECM-derived cues that dictate structural and functional properties of the microvasculature, along with the development of new therapeutic strategies addressing the ECM-dependent regulation of pathophysiological stiffening of blood vessels in ischemic retinopathies.
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Jorgenson, Amy J., Kyoung Moo Choi, Delphine Sicard, Karry M. J. Smith, Samantha E. Hiemer, Xaralabos Varelas, and Daniel J. Tschumperlin. "TAZ activation drives fibroblast spheroid growth, expression of profibrotic paracrine signals, and context-dependent ECM gene expression." American Journal of Physiology-Cell Physiology 312, no. 3 (March 1, 2017): C277—C285. http://dx.doi.org/10.1152/ajpcell.00205.2016.
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Recent studies have implicated the Hippo pathway and its transcriptional effectors YAP and TAZ as necessary for fibroblast activation and tissue fibrosis. To test the specific and sufficient roles for TAZ in driving autonomous fibroblast activation, we cultured NIH3T3 fibroblasts expressing a doxycycline-inducible nuclear-localized mutant of TAZ (TAZ4SA) in scaffold-free 3D hanging drop spheroids, or on matrices of specified mechanical rigidity. Control NIH3T3 fibroblasts formed spheroids in hanging drop culture that remained stable and neither increased nor decreased in size significantly over 15 days. In contrast, TAZ4SA-transduced fibroblasts grew robustly in spheroid culture, and expressed enhanced levels of genes encoding profibrotic soluble factors connective tissue growth factor (CTGF), endothelin-1 (Et-1), and plasminogen activator inhibitor 1 (PAI-1). However, TAZ4SA expression was unable to enhance expression of extracellular matrix (ECM)-encoding genes Col1a1, Col1a2, Col3a1, or Fn1 in spheroid culture. Micromechanical testing indicated that spheroids composed of either control or TAZ4SA-expressing cells were highly compliant and indistinguishable in mechanical properties. In fibroblasts cultured on 2D matrices of compliance similar to spheroids, TAZ4SA expression was able to enhance contractile force generation, but was unable to enhance ECM gene expression. In contrast, culture on stiff hydrogels potentiated TAZ4SA enhancement of ECM expression. TAZ4SA enhancement of Col1a1 expression on soft matrices was potentiated by TGF-β1, while on stiff matrices it was abrogated by inhibition of myocardin-related transcription factor, demonstrating context-dependent crosstalk of TAZ with these pathways. These findings demonstrate sufficiency of TAZ activation for driving fibroblast proliferation, contraction, and soluble profibrotic factor expression, and mechanical context-dependent crosstalk of TAZ with other pathways in regulating Col1a1 expression.
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Wolska-Gawron, Katarzyna, Joanna Bartosińska, and Dorota Krasowska. "MicroRNA in localized scleroderma: a review of literature." Archives of Dermatological Research 312, no. 5 (October 21, 2019): 317–24. http://dx.doi.org/10.1007/s00403-019-01991-0.
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Abstract Localized scleroderma (LoSc) is rare connective tissue disease that manifests with inflammation and fibrosis of the skin. Depending on the LoSc subtype, adjacent structures such as subcutaneous tissue, fascia, muscles, bones may be affected. The hallmark of fibrosis is tissue remodelling with excess deposition of extracellular matrix proteins (ECM), principally collagens. MicroRNAs (miRNAs) are small, noncoding RNA molecules that consist of 19–24 nucleotides and act as negative regulators of gene expression at the posttranscriptional level. Based on the current articles, approximately 40 microRNAs have been linked to fibrosis in different organs and diseases. The majority of these molecules promote or inhibit fibrosis by targeting connective tissue growth factor (CTGF), extracellular matrix proteins, TGF-β pathway and MAPK (mitogen-activated protein kinase) pathway. Further, particular microRNAs regulate fibrogenesis by altering epithelial-to-mesenchymal transition (EMT) or activating proliferation of myofibroblasts. MiRNAs are relatively stable, detectable in tissues and body fluids (serum, plasma) which suggest that they may serve as beneficial biomarkers to monitor the course of the disease and response to treatment. Herein, we report the present state of knowledge on microRNA expression in localized scleroderma.
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Abalymov, Anatolii, Bogdan Parakhonskiy, and Andre Skirtach. "Polymer- and Hybrid-Based Biomaterials for Interstitial, Connective, Vascular, Nerve, Visceral and Musculoskeletal Tissue Engineering." Polymers 12, no. 3 (March 9, 2020): 620. http://dx.doi.org/10.3390/polym12030620.
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In this review, materials based on polymers and hybrids possessing both organic and inorganic contents for repairing or facilitating cell growth in tissue engineering are discussed. Pure polymer based biomaterials are predominantly used to target soft tissues. Stipulated by possibilities of tuning the composition and concentration of their inorganic content, hybrid materials allow to mimic properties of various types of harder tissues. That leads to the concept of “one-matches-all” referring to materials possessing the same polymeric base, but different inorganic content to enable tissue growth and repair, proliferation of cells, and the formation of the ECM (extra cellular matrix). Furthermore, adding drug delivery carriers to coatings and scaffolds designed with such materials brings additional functionality by encapsulating active molecules, antibacterial agents, and growth factors. We discuss here materials and methods of their assembly from a general perspective together with their applications in various tissue engineering sub-areas: interstitial, connective, vascular, nervous, visceral and musculoskeletal tissues. The overall aims of this review are two-fold: (a) to describe the needs and opportunities in the field of bio-medicine, which should be useful for material scientists, and (b) to present capabilities and resources available in the area of materials, which should be of interest for biologists and medical doctors.
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Riquelme-Guzmán, Camilo, Osvaldo Contreras, and Enrique Brandan. "Expression of CTGF/CCN2 in response to LPA is stimulated by fibrotic extracellular matrix via the integrin/FAK axis." American Journal of Physiology-Cell Physiology 314, no. 4 (April 1, 2018): C415—C427. http://dx.doi.org/10.1152/ajpcell.00013.2017.
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Fibrosis is a common feature of several chronic diseases and is characterized by exacerbated accumulation of ECM. An understanding of the cellular and molecular mechanisms involved in the development of this condition is crucial for designing efficient treatments for those pathologies. Connective tissue growth factor (CTGF/CCN2) is a pleiotropic protein with strong profibrotic activity. In this report, we present experimental evidence showing that ECM stimulates the synthesis of CTGF in response to lysophosphatidic acid (LPA).The integrin/focal adhesion kinase (FAK) signaling pathway mediates this effect, since CTGF expression is abolished by the use of the Arg-Gly-Asp-Ser peptide and also by an inhibitor of FAK autophosphorylation at tyrosine 397. Cilengitide, a specific inhibitor of αv integrins, inhibits the expression of CTGF mediated by LPA or transforming growth factor β1. We show that ECM obtained from decellularized myofibroblast cultures or derived from activated fibroblasts from muscles of the Duchenne muscular dystrophy mouse model ( mdx) induces the expression of CTGF. This effect is dependent on FAK phosphorylation in response to its activation by integrin. We also found that the fibrotic ECM inhibits skeletal muscle differentiation. This novel regulatory mechanism of CTGF expression could be acting as a positive profibrotic feedback between the ECM and CTGF, revealing a novel concept in the control of fibrosis under chronic damage.
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Wu, Shi-Bei, Tzu-Yu Hou, Hui-Chuan Kau, and Chieh-Chih Tsai. "Effect of Pirfenidone on TGF-β1-Induced Myofibroblast Differentiation and Extracellular Matrix Homeostasis of Human Orbital Fibroblasts in Graves’ Ophthalmopathy." Biomolecules 11, no. 10 (September 29, 2021): 1424. http://dx.doi.org/10.3390/biom11101424.
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Pirfenidone is a pyridinone derivative that has been shown to inhibit fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Its effect on orbital fibroblasts remains poorly understood. We investigated the in vitro effect of pirfenidone in transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation and extracellular matrix (ECM) homeostasis in primary cultured orbital fibroblasts from patients with Graves’ ophthalmopathy (GO). The expression of fibrotic proteins, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin, and collagen type I, was determined by Western blots. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for the ECM homeostasis were examined. After pretreating the GO orbital fibroblasts with pirfenidone (250, 500, and 750 μg/mL, respectively) for one hour followed by TGF-β1 for another 24 h, the expression of α-SMA, CTGF, fibronectin, and collagen type I decreased in a dose-dependent manner. Pretreating the GO orbital fibroblasts with pirfenidone not only abolished TGF-β1-induced TIMP-1 expression but recovered the MMP-2/-9 activities. Notably, pirfenidone inhibited TGF-β1-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), the critical mediators in the TGF-β1 pathways. These findings suggest that pirfenidone modulates TGF-β1-mediated myofibroblast differentiation and ECM homeostasis by attenuating downstream signaling of TGF-β1.
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Liu, Ning, Toshiaki Makino, Fumiaki Nogaki, Hitoshi Kusano, Katsuo Suyama, Eri Muso, Gisho Honda, Toru Kita, and Takahiko Ono. "Coagulation in the mesangial area promotes ECM accumulation through factor V expression in MsPGN in rats." American Journal of Physiology-Renal Physiology 287, no. 4 (October 2004): F612—F620. http://dx.doi.org/10.1152/ajprenal.00322.2003.
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It is well known that tissue factor starts the extrinsic coagulation pathway, which activates factor X to Xa, and factor V is a membrane-bound potent cofactor for the terminating stage of prothrombin activation by factor Xa. In a previous in vitro study, factor V was induced in cultured mesangial cells by inflammatory stimulation and increased expression of factor V promoted fibrin generation on the cultured mesangial cell surface. We report that extracellular matrix (ECM) accumulation is increased in association with coagulation in the mesangial area through factor V expression in mesangioproliferative glomerulonephritis (MsPGN). Wistar rats were intravenously injected with rabbit anti-rat thymocyte serum accompanied with or without simultaneous injection of rabbit anti-factor V antibody. Time course study in immunohistochemistry revealed that factor V expression was prominent on day 3 and fibrin-related antigen (FRA) deposition, then ECM accumulation, followed from day 3 to day 8. Massive fibronectin depositions and transforming growth factor (TGF)-β expression were also noted in glomeruli from the disease control group, markedly higher than those in the normal group, and these depositions and expressions were significantly decreased in the anti-factor V neutralizing antibody-injected group. Northern blot analysis revealed that factor V mRNA expression was prominent on day 3 and was weak on day 8. Double-labeling experiments revealed the frequent colocalization of α-smooth muscle actin with factor V, FRA, and fibronectin in the same mesangial areas of glomeruli. TGF-β, connective tissue growth factor (CTGF), collagen type IV, and fibronectin mRNA were upregulated in the disease control group, and anti-factor V-neutralizing antibody injection suppressed these mRNA expressions in glomeruli. The present results suggest that ECM components accumulation may progress in accordance with coagulation in the mesangial area through mesangial factor V expression and upregulated expression of TGF-β and CTGF in MsPGN.
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Kivelä, Riikka, Heikki Kyröläinen, Harri Selänne, Paavo V. Komi, Heikki Kainulainen, and Veikko Vihko. "A single bout of exercise with high mechanical loading induces the expression of Cyr61/CCN1 and CTGF/CCN2 in human skeletal muscle." Journal of Applied Physiology 103, no. 4 (October 2007): 1395–401. http://dx.doi.org/10.1152/japplphysiol.00531.2007.
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High mechanical loading was hypothesized to induce the expression of angiogenic and/or lymphangiogenic extracellular matrix (ECM) proteins in skeletal muscle. Eight men performed a strenuous exercise protocol, which consisted of 100 unilateral maximal drop jumps followed by submaximal jumping until exhaustion. Muscle biopsies were taken 30 min and 48 h postexercise from the vastus lateralis muscle and analyzed for the following parameters: mRNA and protein expression of ECM-associated CCN proteins [cysteine-rich angiogenic protein 61 (Cyr61)/CCN1, connective tissue growth factor (CTGF)/CCN2], and mRNA expression of vascular endothelial growth factors (VEGFs) and hypoxia-inducible factor-1α. The mRNA expression of Cyr61 and CTGF increased 30 min after the exercise (14- and 2.5-fold, respectively; P < 0.001). Cyr61 remained elevated 48 h postexercise (threefold; P < 0.05). The mRNA levels of VEGF-A, VEGF-B, VEGF-C, VEGF-D, or hypoxia-inducible factor-1α did not change significantly at either 30 min or 48 h postexercise; however, the variation between subjects increased markedly in VEGF-A and VEGF-B mRNA. Cyr61 protein levels were higher at both 30 min and 48 h after the exercise compared with the control ( P < 0.05). Cyr61 and CTGF proteins were localized to muscle fibers and the surrounding ECM by immunohistochemistry. Fast fibers stained more intensively than slow fibers. In conclusion, mechanical loading induces rapid expression of CCN proteins in human skeletal muscle. This may be one of the early mechanisms involved in skeletal muscle remodeling after exercise, since Cyr61 and CTGF regulate the expression of genes involved in angiogenesis and ECM remodeling.
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Yoshikawa, Hiroyuki, Yasuyuki Kihara, Masashi Taguchi, Taizo Yamaguchi, Hayato Nakamura, and Makoto Otsuki. "Role of TGF-β1 in the development of pancreatic fibrosis in Otsuka Long-Evans Tokushima Fatty rats." American Journal of Physiology-Gastrointestinal and Liver Physiology 282, no. 3 (March 1, 2002): G549—G558. http://dx.doi.org/10.1152/ajpgi.00323.2001.
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Recently established Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of naturally occurring obesity diabetes, exhibit progressive accumulation of connective tissue in the pancreas. The present study was designed to determine the pathogenic role of transforming growth factor-β1 (TGF-β1) in the development of pancreatic fibrosis in OLETF rats by investigating the serial changes in the expression of TGF-β1 and extracellular matrix (ECM) in the pancreas. Progressive proliferation of connective tissue arose from the interstitial region surrounding islets at 20 wk of age and extended to the exocrine pancreas adjacent to the islets. TGF-β1 mRNA levels in the pancreas increased at 20 wk of age and reached a peak value at 30 wk of age. Fibronectin (FN) and procollagen types I and III mRNAs peaked at 20 wk of age and remained at higher levels than those in the nondiabetic counterparts Long-Evans Tokushima Otsuka rats until 50 wk of age. Immunoreactivities for TGF-β1 and FN were found in islets of OLETF rats at 20 wk of age and were seen in acinar and interstitial cells at 50 wk of age. Moreover, α-smooth muscle actin was located at interstitial region surrounding the islets. Proliferation of the connective tissue in the pancreas of OLETF rats closely correlated with expression of TGF-β1 and ECM. Our results suggest that the development of pancreatic fibrosis in OLETF rats extends from endocrine to exocrine pancreas and that TGF-β1 is involved in pancreatic fibrosis of OLETF rats.
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Leerink, Jan M., Mabel van de Ruit, Elizabeth A. M. Feijen, Leontien C. M. Kremer, Annelies M. C. Mavinkurve-Groothuis, Yigal M. Pinto, Esther E. Creemers, and Wouter E. M. Kok. "Extracellular matrix remodeling in animal models of anthracycline-induced cardiomyopathy: a meta-analysis." Journal of Molecular Medicine 99, no. 9 (May 29, 2021): 1195–207. http://dx.doi.org/10.1007/s00109-021-02098-8.
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AbstractAs in other cardiomyopathies, extracellular matrix (ECM) remodeling plays an important role in anthracycline-induced cardiomyopathy. To understand the pattern and timing of ECM remodeling pathways, we conducted a systematic review in which we describe protein and mRNA markers for ECM remodeling that are differentially expressed in the hearts of animals with anthracycline-induced cardiomyopathy. We included 68 studies in mice, rats, rabbits, and pigs with follow-up of 0.1–8.2 human equivalent years after anthracycline administration. Using meta-analysis, we found 29 proteins and 11 mRNAs that were differentially expressed in anthracycline-induced cardiomyopathy compared to controls. Collagens, matrix metalloproteinases (MMPs), inflammation markers, transforming growth factor ß signaling markers, and markers for cardiac hypertrophy were upregulated, whereas the protein kinase B (AKT) pro-survival pathway was downregulated. Their expression patterns over time from single time point studies were studied with meta-regression using human equivalent years as the time scale. Connective tissue growth factor showed an early peak in expression but remained upregulated at all studied time points. Brain natriuretic peptide (BNP) and MMP9 protein levels increased in studies with longer follow-up. Significant associations were found for higher atrial natriuretic peptide with interstitial fibrosis and for higher BNP and MMP2 protein levels with left ventricular systolic function.
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Sun, Xuyang, Xiaoying Gu, Jingna Peng, Liguo Yang, Xinxin Zhang, Zaohong Ran, and Jiajun Xiong. "PRDX2 Knockdown Inhibits Extracellular Matrix Synthesis of Chondrocytes by Inhibiting Wnt5a/YAP1/CTGF and Activating IL-6/JAK2/STAT3 Pathways in Deer Antler." International Journal of Molecular Sciences 23, no. 9 (May 7, 2022): 5232. http://dx.doi.org/10.3390/ijms23095232.
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Although peroxiredoxin 2 (PRDX2) plays a vital role in relieving oxidative stress, its physiological function in cartilage development remains almost unknown. In this study, we found that the expression of PRDX2 significantly increased in the chondrocytes compared with pre-chondrocytes. PRDX2 knockdown significantly decreased the expression of extracellular matrix (ECM) protein (Col2a and Aggrecan), which led to blocked cartilage formation. Moreover, PRDX2 knockdown also inhibited the expression of connective tissue growth factor (CTGF). CTGF is an important growth factor that regulates synthesis of ECM proteins. We explored the possible regulatory mechanism by which PRDX2 regulated the expression of CTGF. Our results demonstrated that PRDX2 knockdown downregulated the expression of CTGF by inhibiting Wnt5a/Yes-associated protein 1 (YAP1) pathway. In addition, PRDX2 knockdown promoted the expression of interleukin 6 (IL-6), indicating PRDX2 expression had an anti-inflammatory function during antler growth. Mechanistically, PRDX2 knockdown promoted cartilage matrix degradation by activating the IL-6-mediated Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway. These results reveal that PRDX2 is a potential regulator that promotes cartilage extracellular matrix synthesis.
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Frati, Alessia, Barbara Ricci, Federica Pierucci, Silvia Nistri, Daniele Bani, and Elisabetta Meacci. "Role of Sphingosine Kinase/S1P Axis in ECM Remodeling of Cardiac Cells Elicited by Relaxin." Molecular Endocrinology 29, no. 1 (January 1, 2015): 53–67. http://dx.doi.org/10.1210/me.2014-1201.
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Abstract The initiation and progression of heart failure is linked to adverse cardiac remodeling of the extracellular matrix (ECM) during disease mainly through the deregulation of myocardial metalloproteinases (MMPs). Relaxin (RLX), a peptide hormone acting as a physiological cardiac effector, is a key regulator of ECM remodeling in reproductive and nonreproductive tissues. Studying primary cultures of mouse cardiac muscle cells and rat H9c2 cardiomyoblasts, we have obtained evidence for a new signaling pathway activated by RLX to induce ECM remodeling that involves the bioactive sphingolipids sphingosine-1-phosphate (S1P) and ceramide. In both cell populations, recombinant human RLX increased sphingosine kinase activity and S1P formation, whereas sphingomyelin and ceramide content were decreased in [3H]serine-labeled cells. According to the literature, RLX promoted MMP-2 and MMP-9 expression/release. Pharmacological inhibition of sphingolipid metabolism and silencing of sphingosine kinase 1, the enzyme responsible for S1P formation, were able to prevent MMP expression/release elicited by the hormone and induce the expression of tissue inhibitor of MMPs. In addition, we found that sphingolipid signaling is required for the regulation of connective tissue growth factor, a member of the CCN 1–3 family of genes that are involved in cell proliferation and differentiation. Finally, the induction of cardiomyoblast maturation induced by RLX was also found to be counteracted by inhibition of S1P formation. In conclusion, these findings provide a novel mechanism by which RLX acts on cardiac ECM remodeling and cardiac cell differentiation and offer interesting therapeutic options to prevent heart fibrosis and to favor myocardial regeneration.
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Jensen, Sacha A., and Penny A. Handford. "New insights into the structure, assembly and biological roles of 10–12 nm connective tissue microfibrils from fibrillin-1 studies." Biochemical Journal 473, no. 7 (March 29, 2016): 827–38. http://dx.doi.org/10.1042/bj20151108.
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The 10–12 nm diameter microfibrils of the extracellular matrix (ECM) impart both structural and regulatory properties to load-bearing connective tissues. The main protein component is the calcium-dependent glycoprotein fibrillin, which assembles into microfibrils at the cell surface in a highly regulated process involving specific proteolysis, multimerization and glycosaminoglycan interactions. In higher metazoans, microfibrils act as a framework for elastin deposition and modification, resulting in the formation of elastic fibres, but they can also occur in elastin-free tissues where they perform structural roles. Fibrillin microfibrils are further engaged in a number of cell matrix interactions such as with integrins, bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β (TGFβ). Fibrillin-1 (FBN1) mutations are associated with a range of heritable connective disorders, including Marfan syndrome (MFS) and the acromelic dysplasias, suggesting that the roles of 10–12 nm diameter microfibrils are pleiotropic. In recent years the use of molecular, cellular and whole-organism studies has revealed that the microfibril is not just a structural component of the ECM, but through its network of cell and matrix interactions it can exert profound regulatory effects on cell function. In this review we assess what is known about the molecular properties of fibrillin that enable it to assemble into the 10–12 nm diameter microfibril and perform such diverse roles.
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Hou, Tzu-Yu, Shi-Bei Wu, Hui-Chuan Kau, and Chieh-Chih Tsai. "JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts." International Journal of Molecular Sciences 22, no. 6 (March 14, 2021): 2952. http://dx.doi.org/10.3390/ijms22062952.
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Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.
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Li, Min, Yichuan Jiang, Wuhui Jing, Bo Sun, Chunsheng Miao, and Liqun Ren. "Quercetin provides greater cardioprotective effect than its glycoside derivative rutin on isoproterenol-induced cardiac fibrosis in the rat." Canadian Journal of Physiology and Pharmacology 91, no. 11 (November 2013): 951–59. http://dx.doi.org/10.1139/cjpp-2012-0432.
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Quercetin exhibits numerous pharmacological effects, including the capacity for cardioprotection. This study aimed to investigate whether quercetin or its glycoside derivative rutin has any protective action against isoproterenol (ISO) induced cardiac fibrosis, and investigate the structure–activity relationship. Male Wistar rats were injected subcutaneously with ISO (15 mg·(kg body mass)−1) to induce experimental cardiac fibrosis. The cardioprotective effect of co-treatment with quercetin (25 or 50 mg·kg−1) or rutin (25 or 50 mg·kg−1) was investigated in ISO-induced cardiac fibrosis in rats. The administration of quercetin and rutin signifcantly decreased the cardiac weight index and myocardial enzyme activity, increased the activity of superoxide dismutase in the serum, and inhibited the ISO-induced increase in angiotensin II and aldosterone in the plasma. Furthermore, overexpression of transforming growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), and excessive deposition of extracellular matrix (ECM) in isoproterenol-treated myocardial tissues were normalized by quercetin and rutin. Our results suggest that both quercetin and rutin exhibited cardioprotective effects in cardiac fibrosis induced by ISO in the rat heart. Moreover, the effects of rutin are weaker than quercetin at the same dose. The mechanism of these effects may be related to antioxidative stress, inhibition of the renin–angiotensin–aldosterone system, decrease in the expression of TGF-β1 and CTGF, and the subsequent reduction in the deposition of the ECM.
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Li, Bo, Yue Zhou, Jing Chen, Tingting Wang, Zhijuan Li, Yili Fu, Aixia Zhai, and Changlong Bi. "Long non-coding RNA H19 contributes to wound healing of diabetic foot ulcer." Journal of Molecular Endocrinology 65, no. 3 (October 2020): 69–84. http://dx.doi.org/10.1530/jme-19-0242.
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Diabetic foot ulcer (DFU) is a chronic and non-healing complication of diabetes that leads to high hospital costs and, in extreme cases, to amputation. Recent studies have reported that long non-coding RNAs (lncRNAs) are linked to various diabetes-related symptoms. Thus, we aim to explore the role of lncRNA H19 in the wound healing process following DFU. Fibroblasts were isolated from the ulcer margin tissues of DFU patients, with the expression of lncRNA H19, connective tissue growth factor (CTGF) or serum response factor (SRF) altered by lentivirus infection. Next, rat models of DFU induced by high glucose and lipid diet were established, which was also infected with the corresponding lentivirus. The interaction among lncRNA H19, SRF and CTGF was determined. Afterward, cell proliferation and apoptosis, angiogenesis, ECM remodeling and wound healing in DFU tissues were evaluated to explore the effects of lncRNA H19/SRF/CTGF and MAPK signaling pathway on DFU. CTGF was poorly expressed in ulcer tissues from DFU rats and patients. CTGF overexpression was shown to activate the MAPK signaling pathway to promote cell proliferation, ECM remodeling, angiogenesis and wound healing while inhibiting cell apoptosis. lncRNA H19 was validated to elevate CTGF expression by recruiting SRF to the promoter region of CTGF, thus accelerating cell proliferation, ECM remodeling and wound healing while repressing cell apoptosis. Furthermore, MAPK signaling pathway activation is confirmed to be the underlying mechanism behind lncRNA H19/CTGF/SRF-induced results. Thus, lncRNA H19 accelerated wound healing in DFU through elevation of CTGF and activation of the MAPK signaling pathway.
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Perera, Candida N., Hwei G. Chin, Nadire Duru, and Ignacio G. Camarillo. "Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression." Journal of Endocrinology 199, no. 2 (August 20, 2008): 221–33. http://dx.doi.org/10.1677/joe-08-0215.
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Obesity is a recently established risk factor for breast cancer incidence and mortality. A characteristic of obesity is elevated circulating levels of adipocyte-derived hormone leptin. Evidence indicates that leptin plays an important role in mammary tumor formation; however, the mechanisms involved are poorly understood. Toward better defining the role of leptin in breast cancer, we describe the identification of leptin-regulated genes in hormone-responsive Michigan Cancer Foundation-7 (MCF-7) human breast cancer cells using a microarray system. More than 64 leptin-regulated genes were identified including those for growth factors, cell cycle regulators, extracellular matrix (ECM) proteins, and genes associated with metastasis. Cell cycle genes up-regulated by leptin include cyclins D and G, cyclin-dependent kinase 2, p21, p27, and p16. Leptin suppressed the expression of transforming growth factor-β , a cell cycle suppressor. Determining the significance of this effect, treatment of MCF-7 cells with TGFB1 abrogated leptin-stimulated proliferation. Leptin up-regulated the expression of connective tissue growth factor, villin 2, and basigin, factors that are associated with ECM and are known to impact tumor growth. Finally, leptin induced the expression of anti-apoptotic genes BCL2 and survivin, and reduced the expression of apoptotic genes. The effect of leptin on MCF-7 survival was evaluated via TUNEL assay and demonstrated a sixfold reduction in apoptosis in leptin-treated cells, compared with controls. These data suggest leptin promotes mammary tumor growth through multiple mechanisms, including regulating the cell cycle, apoptosis, and by modulating the extracellular environment. The identification of leptin-regulated genes begins to provide mechanistic links into the relationship between obesity and breast cancer incidence and morbidity.
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Wang, Shinong, and Raimund Hirschberg. "BMP7 antagonizes TGF-β-dependent fibrogenesis in mesangial cells." American Journal of Physiology-Renal Physiology 284, no. 5 (May 1, 2003): F1006—F1013. http://dx.doi.org/10.1152/ajprenal.00382.2002.
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Exogenous administration of recombinant human bone morphogenetic protein (BMP)-7 was recently shown to ameliorate renal glomerular and interstitial fibrosis in rodents with experimental renal diseases. We tested the hypothesis that BMP7 functions by antagonizing profibrogenic events that are induced by transforming growth factor (TGF)-β in cultured mesangial cells. Incubation of murine mesangial cells with TGF-β (50–200 pM) increased cell-associated collagen type IV and fibronectin, soluble collagen type IV, thrombospondin, and connective tissue growth factor (CTGF). Coincubation with recombinant human BMP7 (200 pM) reduced the increase of these ECM proteins and CTGF. The changes in collagen type IV and fibronectin proteins occurred without concomitant changes in collagen type α1IV and fibronectin mRNA levels, suggesting that TGF-β and BMP7 act primarily by affecting ECM protein degradation. Indeed, TGF-β decreases the levels and activity of matrix metalloprotease (MMP)-2, the major metalloprotease that is secreted by mesangial cells. Moreover, BMP7 inhibits TGF-β-induced activation of MMP2. Because TGF-β reduces the activity of MMPs through increasing plasminogen activator inhibitor (PAI)-1, we tested whether BMP7 interferes with this TGF-β effect. BMP7 reduces, by about two-thirds, the activation of a PAI-1 promoter/luciferase reporter in cells stably transfected with this construct. The findings from these studies indicate that BMP7 reduces TGF-β-induced ECM protein accumulation in cultured mesangial cells primarily by maintaining levels and activity of MMP2 partially through prevention of TGF-β-dependent upregulation of PAI-1.
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Jin, Yingli, Yan Shi, Yinggang Zou, Chunsheng Miao, Bo Sun, and Cai Li. "Fenugreek Prevents the Development of STZ-Induced Diabetic Nephropathy in a Rat Model of Diabetes." Evidence-Based Complementary and Alternative Medicine 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/259368.
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The present study aims to examine the protective effect of fenugreek and the underlying mechanism against the development of diabetic nephropathy (DN) in streptozotocin- (STZ-) induced diabetic rats. A rat model of diabetes was successfully established by direct injection of STZ and then the rats were administered an interventional treatment of fenugreek. Parameters of renal function, including blood glucose, albuminuria, hemoglobin A1c (HbA1c), dimethyl formamide (DMF), blood urine nitrogen (BUN), serum creatinine (Scr), and kidney index (KI), were detected in the three groups (Con, DN, and DF). Oxidative stress was determined by the activity of antioxidase. Extracellular matrix (ECM) accumulation and other morphological alterations were evaluated by means of immunohistochemistry and electron microscope. Quantitive (q)PCR was employed to detect the mRNA expression of transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF) and protein expression was determined with western blot analysis. DN rats in the present study demonstrated a significant renal dysfunction, ECM accumulation, pathological alteration, and oxidative stress, while the symptoms were evidently reduced by fenugreek treatment. Furthermore, the upregulation of TGF-β1 and CTGF at a transcriptional and translational level in DN rats was distinctly inhibited by fenugreek. Consequently, fenugreek prevents DN development in a STZ-induced diabetic rat model.
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Ramos, Harry, Sandra Galoforo, Yuan You, Ira Seth Winer, Gil Mor, Ayesha Alvero, and Radhika Gogoi. "Connective tissue growth factor expression maintains the epithelial phenotype of ovarian cancer in early epithelial to mesenchymal transition." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e17544-e17544. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e17544.
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e17544 Background: Epithelial to Mesenchymal Transition (EMT) is essential to the process of metastasis in ovarian cancer (OC). Early expressions of proteins and pathways during EMT essential for understanding mechanism and potential therapeutic targets in OC. The aim of our study is to evaluate the role and mechanism of Connective Tissue Growth Factor (CTGF) in OC. Methods: R182 and R2615 are well-characterized epithelial OC cell lines. CTGF expression +/- Transforming Growth Factor -b (TGF-b) was determined via Western blot. R182 and R2615 CTGF knock out (KO) were derived utilizing a Cas9/CRISPR-Cas9 lentivirus plasmid vector and confirmed via PCR. Anoikis resistance and invasion assays were performed to characterize phenotypes of R182 and R2615 wild type (WT) and KO cells. For anoikis resistance, cells were plated in triplicate in an ultra-low adhesive (ULA) cell plate Promega CellTiter assay which measured cell viability quantified by absorbance at 450 nm at 0, 24, 48, and 72 hrs. For invasion assay, 3000 cells were suspended in 50% reduced growth factor Basement Membrane Extract. Human recombinant CTGF was added at 50 and 100 ng/mL concentrations. Cells were plated in tissue culture plate and placed in Cytation 5/Biospa and imaged at 4-hour interval for up to 6 days. Western blot evaluated expression of mesenchymal markers. Chemo-sensitivity was measured by half maximal inhibitory concentration (IC50) for Cisplatin between the WT and KO cells. RNA sequence analysis was performed for both R182 WT and KO cells and analyzed utilizing iPathway Guide. Results: CTGF is constitutively expressed in R182 and R2615 OC cells line as early as 6 hrs of culture and after 30 min of TGF-b treatment. Loss of CTGF promoted anoikis resistance. At 72 hr, R182 CTGF WT cells displayed 75% viability while R182 KO only have 10% viability. Further, we demonstrated that loss of CTGF increases invasion. Administration of exogeneous CTGF in KO cells suppresses invasion in a dose dependent manner demonstrated. Along with epithelial markers CK-18 and beta-catenin, the KO cells expressed the mesenchymal marker SNAIL. No difference in chemo-sensitivity to Cisplatin was seen between WT and KO in either cell line. RNA sequence analysis identified 1106 out of 14054 differentially expressed genes between the WT and KO cells. PI3KAkt, cell adhesion molecules and ECM receptor interaction were pathway that were most significantly regulated. Conclusions: CTGF expression maintains the epithelial phenotype of OC cells during EMT. Loss of CTGF allows anoikis resistance and invasion which are vital characteristics in the metastatic nature of OC. We suggest that loss of CTGF expression in OC cells could be a biomarker for more aggressive OC.
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Ramos, Harry, Sandra Galoforo, Yuan You, Ira Seth Winer, Gil Mor, Ayesha Alvero, and Radhika Gogoi. "Connective tissue growth factor expression maintains the epithelial phenotype of ovarian cancer in early epithelial to mesenchymal transition." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e17544-e17544. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e17544.
Full textAbstract:
e17544 Background: Epithelial to Mesenchymal Transition (EMT) is essential to the process of metastasis in ovarian cancer (OC). Early expressions of proteins and pathways during EMT essential for understanding mechanism and potential therapeutic targets in OC. The aim of our study is to evaluate the role and mechanism of Connective Tissue Growth Factor (CTGF) in OC. Methods: R182 and R2615 are well-characterized epithelial OC cell lines. CTGF expression +/- Transforming Growth Factor -b (TGF-b) was determined via Western blot. R182 and R2615 CTGF knock out (KO) were derived utilizing a Cas9/CRISPR-Cas9 lentivirus plasmid vector and confirmed via PCR. Anoikis resistance and invasion assays were performed to characterize phenotypes of R182 and R2615 wild type (WT) and KO cells. For anoikis resistance, cells were plated in triplicate in an ultra-low adhesive (ULA) cell plate Promega CellTiter assay which measured cell viability quantified by absorbance at 450 nm at 0, 24, 48, and 72 hrs. For invasion assay, 3000 cells were suspended in 50% reduced growth factor Basement Membrane Extract. Human recombinant CTGF was added at 50 and 100 ng/mL concentrations. Cells were plated in tissue culture plate and placed in Cytation 5/Biospa and imaged at 4-hour interval for up to 6 days. Western blot evaluated expression of mesenchymal markers. Chemo-sensitivity was measured by half maximal inhibitory concentration (IC50) for Cisplatin between the WT and KO cells. RNA sequence analysis was performed for both R182 WT and KO cells and analyzed utilizing iPathway Guide. Results: CTGF is constitutively expressed in R182 and R2615 OC cells line as early as 6 hrs of culture and after 30 min of TGF-b treatment. Loss of CTGF promoted anoikis resistance. At 72 hr, R182 CTGF WT cells displayed 75% viability while R182 KO only have 10% viability. Further, we demonstrated that loss of CTGF increases invasion. Administration of exogeneous CTGF in KO cells suppresses invasion in a dose dependent manner demonstrated. Along with epithelial markers CK-18 and beta-catenin, the KO cells expressed the mesenchymal marker SNAIL. No difference in chemo-sensitivity to Cisplatin was seen between WT and KO in either cell line. RNA sequence analysis identified 1106 out of 14054 differentially expressed genes between the WT and KO cells. PI3KAkt, cell adhesion molecules and ECM receptor interaction were pathway that were most significantly regulated. Conclusions: CTGF expression maintains the epithelial phenotype of OC cells during EMT. Loss of CTGF allows anoikis resistance and invasion which are vital characteristics in the metastatic nature of OC. We suggest that loss of CTGF expression in OC cells could be a biomarker for more aggressive OC.
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Ezhilararasan, Devaraj, Thangavelu Lakshmi, and Biond Raut. "Novel Nano-Based Drug Delivery Systems Targeting Hepatic Stellate Cells in the Fibrotic Liver." Journal of Nanomaterials 2021 (October 22, 2021): 1–9. http://dx.doi.org/10.1155/2021/4674046.
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Hepatic stellate cells (HSCs) exist in the liver’s perisinusoidal space, are phenotypically activated, and acquire myofibroblast-like phenotype. This phenotypic transformation is accountable for the accumulation and production of various extracellular matrix (ECM) proteins, involving different fibril-forming collagens in the perisinusoidal space, producing altered hepatic function and portal hypertension and increased vascular resistance, fibrosis, cirrhosis, and hepatocellular carcinoma. The activated HSCs/myofibroblasts are principal collagen-producing cells in the damaged liver. Therefore, fibrosis treatments are often targeting HSCs. HSCs store most of the total body’s retinol in their cytoplasm, and hence, antifibrotic nanomedicines are often targeted with vitamin A decoration. Vitamin A-decorated nanomedicines with siRNAs for transforming growth factor-beta, collagen, and connective tissue growth factors target to inhibit fibrogenesis and the ECM-associated gene expressions, leading to fibrosis regression. Similarly, a variety of miRNAs play pro- and antifibrotic function. In the fibrotic liver, the profibrotic miRNAs are targeted with their respective antagomir and the antifibrotic miRNAs are targeted with their respective agomirs along with HSC-specific nanodecoration. These miRNA treatments reduce fibrogenesis by downregulation of ECM-related gene expressions. However, liver fibrosis is caused by the upregulation of a different type of profibrotic signaling pathways associated with ECM accumulation in the fibrotic liver. Therefore, specific gene silencing by siRNAs or targeting particularly miRNA may also not effectively reduce fibrosis to a greater extent. However, nanodecoration of a drug is useful to deliver drugs into activated HSCs in the injured liver. Therefore, the aim of this review is to focus on targeted drug delivery towards activated HSCs in the persistently damaged liver.
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Lai, Thung S., Christopher Davies, and Charles Greenberg. "Tissue Transglutaminase Enhances Fibrin-Dependent Angiogenesis and Extracellular Matrix Formation During Tissue Repair by Altering Gene Expression and Is Inhibited by Aspirin." Blood 114, no. 22 (November 20, 2009): 3055. http://dx.doi.org/10.1182/blood.v114.22.3055.3055.
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Abstract Abstract 3055 Poster Board II-1031 Fibrin deposition triggers an injury response that involves the migration of inflammatory cells, formation of new blood vessels and the synthesis of extracellular matrix (ECM). Tissue transglutaminase (TGM2) is a calcium dependent enzyme that covalently crosslinks a wide variety of ECM proteins producing a protease resistant matrix. TGM2 is secreted by inflammatory and endothelial cells, involved in activating transforming growth factor beta-1 (TGFbeta-1) and expressed during tissue injury. In this study, we investigated how TGM2 modulated fibrin-dependent wound healing and the associated angiogenic response. We used an animal model consisting of fibrin Z-chambers (F-ZC, dual porous plexiglass chambers containing fibrin) implanted into the subcutaneous tissue of rats and harvested subsequently for quantitative assessment of granulation tissue formation (wound healing) and microvessel density (angiogenesis). We found that local administration of recombinant TGM2 into F-ZC resulted in a dose-dependent, 2-fold increase in granulation tissue thickness by day 6 of wound healing (p<0.001), an effect similar in magnitude to 25 ng/ml of TGFbeta1 administered in the F-ZC. The pro-healing effect of TGM2 was associated with a 2-fold increase in microvessel density in granulation tissue at day 6 of wound healing response (p<0.001). As a negative control, inactive recombinant C277A/TGM2 mutant did not exhibit increased wound healing response or proangiogenic effect. The data suggested that TGM2 enhanced the transition from the inflammatory stage of wound healing to proliferation stage. The two areas where TGM2 enhanced wound healing were 1) angiogenesis and 2) deposition of ECM. To investigate TGM2-induced angiogenesis-related gene expression, total RNAs were isolated from control- and TGM2-treated F-ZCs (at Day 6). Biotin-labeled cDNA probes were synthesized, and hybridized to nylon membranes containing angiogenesis-related gene arrays (Superarray, MD). The signals were detected using streptavidin-peroxidase and quantitated. We identified increased expression of VEGF receptors Flk-1 (2-fold), Flt1 and neuropilin (1.4-fold), angiopoietin-1 (2-fold) and ephrin B2 (1.8-fold). There were decreased levels (5-fold) of matrix metalloproteinases (MMPs) and increased TGFbeta-1 receptors (1.5-fold) and connective tissue growth factor (CTGF)(1.4-fold) levels. The gene expression profile suggests that TGM2 promotes angiogenesis and enhances deposition of ECM. We then investigated whether Aspirin (Acetylsalicylic Acid, ASA) a potent anti-inflammatory agent would inhibit TGM2. ASA and another chemical acetylating agent, sulfosuccinimidyl acetate (SNA), were used to investigate whether acetylation would alter the crosslinking activity of TGM2. We found acetylation by either SNA or ASA resulted in a loss of >90% of crosslinking activity. The Lys residues that were critical for inhibition were identified by mass spectrometry as Lys468 and Lys663. Molecular modeling indicates that these Lys residues play an important role in the conformation change that occurs in TGM2 from a closed-to-open shape, i.e. inactive-to-active, transitions. In conclusion, we show that TGM2-fibrin crosslinking accelerates angiogenesis and promotes ECM deposition. This suggests that TGM2-fibrin interactions mediates outside-in signaling events that aides wound healing. Furthermore aspirin can acetylate and inhibit critical residues in TGM2 that regulate TGM-2 function. Disclosures No relevant conflicts of interest to declare.
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Zhang, Xiao-Ping, Feng Zhang, Zi-Li Zhang, Jin Ma, De-Song Kong, Guang-Xia Ni, Ai-Yun Wang, Wen-Xing Chen, Yin Lu, and Shi-Zhong Zheng. "Acupuncture Combined with Curcumin Disrupts Platelet-Derived Growth Factor β Receptor/Extracellular Signal-Regulated Kinase Signalling and Stimulates Extracellular Matrix Degradation in Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats." Acupuncture in Medicine 30, no. 4 (December 2012): 324–30. http://dx.doi.org/10.1136/acupmed-2012-010167.
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Background Acupuncture treatment has been increasingly used to treat chronic liver diseases. We previously reported that acupuncture combined with curcumin, a natural antifibrotic compound, could remarkably attenuate liver fibrosis in chemically intoxicated rats, but the underlying molecular mechanisms are poorly understood. The present study was aimed at investigating the effects of acupuncture combined with curcumin on platelet-derived growth factor (PDGF) signalling and extracellular matrix (ECM) regulation in the fibrotic liver. Methods A total of 60 Sprague-Dawley male rats were randomly divided into control, model, sham, acupuncture, curcumin and combination treatment groups. During the establishment of fibrosis using carbon tetrachloride (CCl4), acupuncture at LR3, LR14, BL18 and ST36 and/or curcumin treatment by mouth were performed simultaneously. After treatment, serum PDGF levels were measured. Protein and mRNA expression of key effectors in PDGF pathway and fibrinolysis in the liver was determined. Results Acupuncture combined with curcumin potently reduced serum PDGF levels and selectively disrupted the PDGF-βR/extracellular signal-regulated kinase (ERK) cascade. Combination treatment also significantly repressed expression of connective tissue growth factor and upregulated expression of matrix metalloproteinase-9, promoting fibrinolysis in the fibrotic liver. Conclusions The beneficial effects of acupuncture and its combination with curcumin could be attributed to the disruption of PDGF-βR/ERK pathway and stimulated ECM degradation in the fibrotic liver. Acupuncture treatment significantly enhanced curcumin effects at the molecular level. These findings may provide molecular insights into the potential of acupuncture combined with curcumin for prevention of hepatic fibrosis.
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Zhou, Bing, Li Ling, Feng Zhang, Tong-Yan Liu, Hong Zhou, Xiao-Hong Qi, Qi Chen, Yue-Hua Li, Yu-Ming Kang, and Guo-Qing Zhu. "Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis Via Inhibition of Hepatic Stellate Cell Activation." Cellular Physiology and Biochemistry 48, no. 1 (2018): 227–36. http://dx.doi.org/10.1159/000491722.
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Background/Aims: Fibronectin type III domain-containing 5 (FNDC5) protein is involved in the beneficial effects of exercise on metabolism. FNDC5 attenuates hepatic steatosis induced by high fat diet (HFD). Here, we examined the effects of FNDC5 on liver fibrosis and underline mechanisms. Methods: Experiments were carried out on wild-type and FNDC5-/- mice, primary mouse hepatic stellate cells (HSCs) and human hepatic stellate cell line (LX-2). The mice were fed with HFD for 6 months to induce liver fibrosis. Oxidized low density lipoprotein (oxLDL) were used to induce the activation of hepatic stellate cells and fibrosis in mouse HSCs and human LX-2 cells. H&E, Masson’s trichrome staining and Sirius red staining were used for liver sections. Protein and mRNA expressions were evaluated with Western blot and RT-PCR, respectively. Results: FNDC5 deficiency aggravated the HFD-induced liver fibrosis and HSCs activation in mice. It exacerbated the HFD-induced inhibition of AMPK phosphorylation, upregulation of connective tissue growth factor (CTGF) and transforming growth factor-β (TGF-β), and deposition of extracellular matrix (ECM) in liver of mice. Administration of FNDC5 attenuated oxLDL-induced AMPK deactivation, HSCs activation, CTGF and TGF-β upregulation and ECM deposition in mouse HSCs. The beneficial effects of FNDC5 on oxLDL-induced AMPK dephosphorylation, HSCs activation and ECM deposition were prevented by the inhibition of AMPK with compound C in human LX-2 cells. However, the effects of FNDC5 on hepatic fibrosis in vivo in this study cannot be distinguished from its effects on adiposity and hepatic steatosis. Conclusions: FNDC5 deficiency aggravates HFD-induced liver fibrosis in mice. FNDC5 plays beneficial roles in attenuating liver fibrosis via AMPK phosphorylation-mediated inhibition of HSCs activation.
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Al-U’datt, Doa’a G. F., Carole C. Tranchant, Belal Al-Husein, Roddy Hiram, Ahmed Al-Dwairi, Mohammad AlQudah, Othman Al-shboul, Saied Jaradat, Jenan Alqbelat, and Ali Almajwal. "Involvement and possible role of transglutaminases 1 and 2 in mediating fibrotic signalling, collagen cross-linking and cell proliferation in neonatal rat ventricular fibroblasts." PLOS ONE 18, no. 2 (February 27, 2023): e0281320. http://dx.doi.org/10.1371/journal.pone.0281320.
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Transglutaminase (TG) isoforms control diverse normal and pathophysiologic processes through their capacity to cross-link extracellular matrix (ECM) proteins. Their functional and signalling roles in cardiac fibrosis remain poorly understood, despite some evidence of TG2 involvement in abnormal ECM remodelling in heart diseases. In this study, we investigated the role of TG1 and TG2 in mediating fibrotic signalling, collagen cross-linking, and cell proliferation in healthy fibroblasts by siRNA-mediated knockdown. siRNA for TG1, TG2 or negative control was transfected into cultured neonatal rat ventricular fibroblasts and cardiomyocytes. mRNA expression of TGs and profibrotic, proliferation and apoptotic markers was assessed by qPCR. Cell proliferation and soluble and insoluble collagen were determined by ELISA and LC-MS/MS, respectively. TG1 and TG2 were both expressed in neonatal rat cardiomyocytes and fibroblasts before transfection. Other TGs were not detected before and after transfection. TG2 was predominantly expressed and more effectively silenced than TG1. Knocking down TG1 or TG2 significantly modified profibrotic markers mRNA expression in fibroblasts, decreasing connective tissue growth factor (CTGF) and increasing transforming growth factor-β1 compared to the negative siRNA control. Reduced expression of collagen 3A1 was found upon TG1 knockdown, while TG2 knockdown raised α-smooth muscle actin expression. TG2 knockdown further increased fibroblast proliferation and the expression of proliferation marker cyclin D1. Lower insoluble collagen content and collagen cross-linking were evidenced upon silencing TG1 or TG2. Transcript levels of collagen 1A1, fibronectin 1, matrix metalloproteinase-2, cyclin E2, and BCL-2-associated X protein/B-cell lymphoma 2 ratio were strongly correlated with TG1 mRNA expression, whereas TG2 expression correlated strongly with CTGF mRNA abundance. These findings support a functional and signalling role for TG1 and TG2 from fibroblasts in regulating key processes underlying myocardial ECM homeostasis and dysregulation, suggesting that these isoforms could be potential and promising targets for the development of cardiac fibrosis therapies.
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Haroon, Zishan A., Thung S. Lai, and Charles S. Greenberg. "Tissue Transglutaminase Enhances Fibrin-Dependent Angiogenesis and Extracellular Matrix Formation by Altering Gene Expression during Wound Healing." Blood 104, no. 11 (November 16, 2004): 2626. http://dx.doi.org/10.1182/blood.v104.11.2626.2626.
Full textAbstract:
Abstract Fibrin deposition triggers an injury response that involves the migration of inflammatory cells formation of new blood vessels and the synthesis of extracellular matrix (ECM). Tissue transglutaminase (TTG) is a calcium dependent enzyme that covalently crosslinks a wide variety of ECM proteins producing a protease resistant matrix. TTG is secreted by inflammatory and endothelial cells, involved in activating transforming growth factor beta-1 (TGF beta-1) and expressed during wound healing response. In this study, we investigated how TTG modulated fibrin-dependent wound healing and the associated angiogenic response. We used an animal model consisting of fibrin Z-chambers (F-ZC, dual porous plexiglass chambers containing fibrin), implanted into the subcutaneous tissue of rats and harvested subsequently for quantitative assessment of granulation tissue formation (wound healing) and microvessel density (angiogenesis). We found that local administration of recombinant TTG into F-ZC resulted in a dose-dependent, 2-fold increase in granulation tissue thickness by day 6 of wound healing (p<0.001), an effect similar in magnitude to 25 ng/ml of TGFbeta1 administered in the F-ZC. The pro-healing effect of TTG was associated with a 2-fold increase in microvessel density in granulation tissue at day 6 of wound healing response (p<0.001). As a negative control, inactive recombinant TTG mutant did not exhibit increased wound healing response or pro-angiogenic effect. The data suggested that TTG enhanced the transition from the inflammatory stage of wound healing to proliferation stage. The two areas where TTG enhanced wound healing were 1) angiogenesis and 2) deposition of matrix. To investigate TTG-induced gene expression, total RNAs were isolated from control- and TTG-treated F-ZCs (at Day 6) using Trizol reagent (Invitrogen, CA). Biotin-labeled cDNA probes were synthesized, and hybridized to nylon membranes containing angiogenesis-related gene arrays (Superarray, MD). The signals were detected using streptavidin-peroxidase and quantitated using Superarray’s software. We identified increased expression of VEGF receptors Flk-1, Flt1 and neuropilin, suggesting increased responsiveness to the potent angiogenic factor VEGF. In addition, increased levels of angiopoietin-1 and ephrin B2 were observed which are involved in vascular development and stabilization. For matrix enhancing effects, considerably decreased levels (5-fold) of matrix metalloproteinases (MMPs) coupled with increased TGFbeta receptors and connective tissue growth factor (CTGF) were observed. The gene expression profile suggests that TTG alters the balance between matrix production and destruction in favor of production resulting in increased deposition of ECM in granulation tissue. In conclusion, we have identified that TTG 1) enhances fibrin-dependent wound healing response, 2) increases angiogenesis through enhanced VEGF receptors, angiopoietin-1 and ephrin B2 expression, and 3) promoted matrix deposition by simultaneously reducing MMPs and increasing CTGF and TGFbeta receptors expression.
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Haggart, Charles R., Elizabeth G. Ames, Jae K. Lee, and Jeffrey W. Holmes. "Effects of stretch and shortening on gene expression in intact myocardium." Physiological Genomics 46, no. 2 (January 15, 2014): 57–65. http://dx.doi.org/10.1152/physiolgenomics.00103.2013.
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Multiple cues have been suggested as the mechanical stimulus for the heart's hypertrophic response. Our work has previously suggested that the amount of cyclic shortening in cardiomyocytes controls myocyte shape and the amount of stretch controls myocyte size. To identify gene expression changes that occur in response to these mechanical perturbations, we used microarray analysis of papillary muscles cultured for 12 h at physiological or reduced levels of cyclic shortening and physiological or reduced mean stretch. Overall, genes related to extracellular matrix (ECM) were surprisingly prominent in our analysis. Connective tissue growth factor was among a small group of genes regulated by the amount of cyclic shortening regardless of the level of mean stretch, and many more ECM genes were regulated by shortening with reduced amounts of stretch. When we compared our results to gene expression data from an in vivo model of pressure overload (PO), which also decreases myocyte shortening, we found the genes that were commonly regulated in PO and our decreased shortening groups were most significantly enriched for ontology terms related to the ECM, followed by genes associated with mechanosensing and the cytoskeleton. The list of genes regulated in PO and our decreased shortening groups also includes genes known to change early in hypertrophy, such as myosin heavy chain 7, brain natriuretic peptide, and myosin binding protein C. We conclude that in intact myocardium, the amount of cyclic shortening may be an important regulator not only of myocyte genes classically associated with hypertrophy but also of ECM genes.
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Maharjan, Babu Raja, Susan V. McLennan, Stephen M. Twigg, and Paul F. Williams. "The Effect of TGFβ1 in Adipocyte on Inflammatory and Fibrotic Markers at Different Stages of Adipocyte Differentiation." Pathophysiology 29, no. 4 (November 23, 2022): 640–49. http://dx.doi.org/10.3390/pathophysiology29040050.
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Transforming growth factor beta (TGFβ) is a versatile cytokine. Although a profibrotic role of TGFβ is well established, its effect on tissue inhibitor of metalloproteinase (TIMPs) and inflammatory mediators are incompletely described. This study investigates the profibrotic and pro-inflammatory role of TGFβ1 during adipocyte differentiation. NIH3T3L1 cells were used for the in vitro study and were differentiated by adding a standard differentiation mix either with rosiglitazone (R-Diff) or without (S-Diff). Recombinant TGFβ1 (2 ng/mL) was added to the undifferentiated preadipocyte during the commitment stage and at the terminal differentiation stage. TGFβ1 treatment significantly decreased adiponectin mRNA at both early commitment (>300 fold) and terminal differentiated cells [S-Diff (~33%) or R-Diff (~20%)]. TGFβ1 upregulated collagen VI mRNA and its regulators connective tissue growth factor (CCN2/CTGF), TIMP1 and TIMP3 mRNA levels in undifferentiated preadipocytes and adipocytes at commitment stage. But in the terminal differentiated adipocytes, changes in mRNA and protein of collagen VI and TIMP3 mRNA were not observed despite an increase in CCN2/CTGF, TIMP1 mRNA. Although TGFβ1 upregulated interleukin-6 (IL6) and monocyte chemoattractant protein-1 (MCP1) mRNA at all stages of differentiation, decreased tumor necrosis factor-α (TNFα) mRNA was observed early in adipocyte differentiation. This study highlights the complex role of TGFβ1 on extracellular matrix (ECM) remodeling and inflammatory markers in stimulating both synthetic and inhibitory markers of fibrosis at different stages of adipocyte differentiation.
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Colston, J. T., S. D. de la Rosa, M. Koehler, K. Gonzales, R. Mestril, G. L. Freeman, S. R. Bailey, and B. Chandrasekar. "Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 3 (September 2007): H1839—H1846. http://dx.doi.org/10.1152/ajpheart.00428.2007.
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Wnt1-induced secreted protein-1 (WISP-1) is a member of the cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed (CCN) family of growth factors and is expressed in the heart at low basal levels. The purpose of this study was to investigate whether WISP-1 is upregulated in postinfarct myocardium and whether WISP-1 exerts prohypertrophic and mitogenic effects stimulating myocyte hypertrophy, cardiac fibroblast (CF) proliferation, and collagen expression. Male C57Bl/6 (25 g) mice underwent permanent occlusion of the left anterior descending coronary artery. mRNA and protein levels were analyzed by Northern and Western blot analyses. Cardiomyocyte hypertrophy was quantified by protein and DNA synthesis. CF proliferation was quantified by CyQuant assay, and soluble collagen release by Sircol assay. A time-dependent increase in WISP-1 expression was detected in vivo in the noninfarct zone of the left ventricle, which peaked at 24 h (3.1-fold, P < 0.01). Similarly, biglycan expression was increased by 3.71-fold ( P < 0.01). IL-1β and TNF-α expression preceded WISP-1 expression in vivo and stimulated WISP-1 expression in neonatal rat ventricular myocytes in vitro. WISP-1-induced cardiomyocyte hypertrophy was evidenced by increased protein (2.78-fold), but not DNA synthesis, and enhanced Akt phosphorylation and activity. Treatment of primary CF with WISP-1 significantly stimulated proliferation at 48 h (6,966 ± 264 vs. 5,476 ± 307 cells/well, P < 0.01) and enhanced collagen release by 72 h (18.4 ± 3.1 vs. 8.4 ± 1.0 ng/cell, P < 0.01). Our results demonstrate for the first time that WISP-1 and biglycan are upregulated in the noninfarcted myocardium in vivo, suggesting a positive amplification of WISP-1 signaling. WISP-1 stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and ECM expression in vitro. These results suggest that WISP-1 may play a critical role in post-myocardial infarction remodeling.
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Kurmann, Lisa, Michal Okoniewski, and Raghvendra K. Dubey. "Transcryptomic Analysis of Human Brain -Microvascular Endothelial Cell Driven Changes in -Vascular Pericytes." Cells 10, no. 7 (July 14, 2021): 1784. http://dx.doi.org/10.3390/cells10071784.
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Many pathological conditions of the brain are associated with structural abnormalities within the neurovascular system and linked to pericyte (PC) loss and/or dysfunction. Since crosstalk between endothelial cells (ECs) and PCs greatly impacts the function of the blood–brain barrier (BBB), effects of PCs on endothelial integrity and function have been investigated extensively. However, the impact of ECs on the function and activity of PCs remains largely unknown. Hence, using co-cultures of human brain vascular PCs with human cerebral microvascular ECs on opposite sides of porous Transwell inserts which facilitates direct EC–PC contact and improves EC barrier function, we analyzed EC-driven transcriptomic changes in PCs using microarrays and changes in cytokines/chemokines using proteome arrays. Gene expression analysis (GEA) in PCs co-cultured with ECs versus PCs cultured alone showed significant upregulation of 1′334 genes and downregulation of 964 genes. GEA in co-cultured PCs revealed increased expression of five prominent PC markers as well as soluble factors, such as transforming growth factor beta, fibroblast growth factor, angiopoietin 1, brain-derived neurotrophic factor, all of which are involved in EC–PC crosstalk and BBB induction. Pathway enrichment analysis of modulated genes showed a strong impact on many inflammatory and extracellular matrix (ECM) pathways including interferon and interleukin signaling, TGF-β and interleukin-1 regulation of ECM, as well as on the mRNA processing pathway. Interestingly, while co-culture induced the mRNA expression of many chemokines and cytokines, including several CCL- and CXC-motif ligands and interleukins, we observed a decreased expression of the same inflammatory mediators on the protein level. Importantly, in PCs, ECs significantly induced interferon associated proteins (IFIT1, IFI44L, IF127, IFIT3, IFI6, IFI44) with anti-viral actions; downregulated prostaglandin E receptor 2 (prevent COX-2 mediated BBB damage); upregulated fibulin-3 and connective tissue growth factor essential for BBB integrity; and multiple ECMs (collagens and integrins) that inhibit cell migration. Our findings suggest that via direct contact, ECs prime PCs to induce molecules to promote BBB integrity and cell survival during infection and inflammatory insult. Taken together, we provide first evidence that interaction with ECs though porous membranes induces major changes in the transcriptomic and proteomic profile of PCs. ECs influence genes involved in diverse aspects of PC function including PC maturation, cell survival, anti-viral defense, blood flow regulation, immuno-modulation and ECM deposition.
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Hingert, Daphne, Phonphan Nawilaijaroen, Jonathan Aldridge, Adad Baranto, and Helena Brisby. "Investigation of the Effect of Secreted Factors from Mesenchymal Stem Cells on Disc Cells from Degenerated Discs." Cells Tissues Organs 208, no. 1-2 (2019): 76–88. http://dx.doi.org/10.1159/000506350.
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Low back pain is experienced by a large number of people in western countries and may be caused and influenced by many different pathologies and psychosocial factors including disc degeneration. Disc degeneration involves the increased expression of proinflammatory cytokines and matrix metalloproteinases (MMPs) in the disc environment, which leads to the loss of extracellular matrix (ECM) and the viability of the native disc cells (DCs). Treatment approaches using growth factors and cell therapy have been proposed due to the compelling results that growth factors and mesenchymal stem cells (MSCs) can influence the degenerated discs. The aim of this study was to investigate the effects of conditioned media (CM) from human MSCs (hMSCs) and connective tissue growth factor (CTGF) and TGF-β on disc cells, and hMSCs isolated from patients with degenerative discs and severe low back pain. The aim was also to examine the constituents of CM in order to study the peptides that could bring about intervertebral disc (IVD) regeneration. DCs and hMSC pellets (approx.. 200,000 cells) were cultured and stimulated with hMSC-derived CM or CTGF and TGF-β over 28 days. The effects of CM and CTGF on DCs and hMSCs were assessed via cell viability, proteoglycan production, the expression of ECM proteins, and chondrogenesis in 3D pellet culture. To identify the constituents of CM, CM was analyzed with tandem mass spectrometry. The findings indicate that CM enhanced the cellular viability and ECM production of DCs while CTGF and the control exhibited nonsignificant differences. The same was observed in the hMSC group. Mass spectrometry analysis of CM identified >700 peptides, 129 of which showed a relative abundance of ≥2 (CTGF among them). The results suggest that CM holds potential to counter the progression of disc degeneration, likely resulting from the combination of all the substances released by the hMSCs. The soluble factors released belong to different peptide families. The precise mechanism underlying the regenerative effect needs to be investigated further, prior to incorporating peptides in the development of new treatment strategies for low back pain that is potentially caused by IVD degeneration.
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Antar, Samar A., Nada A. Ashour, Mohamed E. Marawan, and Ahmed A. Al-Karmalawy. "Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation." International Journal of Molecular Sciences 24, no. 4 (February 16, 2023): 4004. http://dx.doi.org/10.3390/ijms24044004.
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Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause fibrosis or scarring. The fibrotic process finally results in organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues of the body. The fibrosis process is associated with chronic inflammation, metabolic homeostasis, and transforming growth factor-β1 (TGF-β1) signaling, where the balance between the oxidant and antioxidant systems appears to be a key modulator in managing these processes. Virtually every organ system, including the lungs, heart, kidney, and liver, can be affected by fibrosis, which is characterized as an excessive accumulation of connective tissue components. Organ malfunction is frequently caused by fibrotic tissue remodeling, which is also frequently linked to high morbidity and mortality. Up to 45% of all fatalities in the industrialized world are caused by fibrosis, which can damage any organ. Long believed to be persistently progressing and irreversible, fibrosis has now been revealed to be a very dynamic process by preclinical models and clinical studies in a variety of organ systems. The pathways from tissue damage to inflammation, fibrosis, and/or malfunction are the main topics of this review. Furthermore, the fibrosis of different organs with their effects was discussed. Finally, we highlight many of the principal mechanisms of fibrosis. These pathways could be considered as promising targets for the development of potential therapies for a variety of important human diseases.