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Marchini, Marta, Elizabeth Silva Hernandez, and Campbell Rolian. "Morphology and development of a novel murine skeletal dysplasia." PeerJ 7 (July 4, 2019): e7180. http://dx.doi.org/10.7717/peerj.7180.
Повний текст джерелаАнотація:
Background Limb bones develop and grow by endochondral ossification, which is regulated by specific cell and molecular pathways. Changes in one or more of these pathways can have severe effects on normal skeletal development, leading to skeletal dysplasias. Many skeletal dysplasias are known to result from mis-expression of major genes involved in skeletal development, but the etiology of many skeletal dysplasias remains unknown. We investigated the morphology and development of a mouse line with an uncharacterized mutation exhibiting a skeletal dysplasia-like phenotype (Nabo). Methods We used µCT scanning and histology to comprehensively characterize the phenotype and its development, and to determine the developmental stage when this phenotype first appears. Results Nabo mice have shorter limb elements compared to wildtype mice, while clavicles and dermal bones of the skull are not affected. Nabo embryos at embryonic stage E14 show shorter limb cartilage condensations. The tibial growth plate in Nabo mice is wider than in wildtype, particularly in the proliferative zone, however proliferative chondrocytes show less activity than wildtype mice. Cell proliferation assays and immunohistochemistry against the chondrogenic marker Sox9 suggest relatively lower, spatially-restricted, chondrocyte proliferation activity in Nabo. Bone volume and trabecular thickness in Nabo tibiae are also decreased compared to wildtype. Discussion Our data suggest that the Nabo mutation affects endochondral ossification only, with the strongest effects manifesting in more proximal limb structures. The phenotype appears before embryonic stage E14, suggesting that outgrowth and patterning processes may be affected. Nabo mice present a combination of skeletal dysplasia-like characteristics not present in any known skeletal dysplasia. Further genomic and molecular analysis will help to identify the genetic basis and precise developmental pathways involved in this unique skeletal dysplasia.
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Xie, Meng, Dmitrii Kamenev, Marketa Kaucka, Maria Eleni Kastriti, Baoyi Zhou, Artem V. Artemov, Mekayla Storer, et al. "Schwann cell precursors contribute to skeletal formation during embryonic development in mice and zebrafish." Proceedings of the National Academy of Sciences 116, no. 30 (July 8, 2019): 15068–73. http://dx.doi.org/10.1073/pnas.1900038116.
Повний текст джерелаАнотація:
Immature multipotent embryonic peripheral glial cells, the Schwann cell precursors (SCPs), differentiate into melanocytes, parasympathetic neurons, chromaffin cells, and dental mesenchymal populations. Here, genetic lineage tracing revealed that, during murine embryonic development, some SCPs detach from nerve fibers to become mesenchymal cells, which differentiate further into chondrocytes and mature osteocytes. This occurred only during embryonic development, producing numerous craniofacial and trunk skeletal elements, without contributing to development of the appendicular skeleton. Formation of chondrocytes from SCPs also occurred in zebrafish, indicating evolutionary conservation. Our findings reveal multipotency of SCPs, providing a developmental link between the nervous system and skeleton.
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Magnani, D. M., E. T. Lyons, T. S. Forde, M. T. Shekhani, V. A. Adarichev, and G. A. Splitter. "Osteoarticular tissue infection and development of skeletal pathology in murine brucellosis." Disease Models & Mechanisms 6, no. 3 (March 8, 2013): 811–18. http://dx.doi.org/10.1242/dmm.011056.
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Yokota, Masaya, Kotaro Suzuki, Daiki Nakagomi, Koji Tokoyoda, Toshinori Nakayama, Hitoshi Kohsaka, Itsuo Iwamoto, and Hiroshi Nakajima. "Crucial roles of mast cells in the development of a murine model of polymyositis (171.20)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 171.20. http://dx.doi.org/10.4049/jimmunol.188.supp.171.20.
Повний текст джерелаАнотація:
Abstract Objective: In addition to a pivotal role of mast cells in allergic diseases, recent data suggest that mast cells play a crucial role in a variety of immune responses. However, their role in the pathogenesis of autoimmune skeletal muscle diseases has not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the role of mast cells in the development of a murine model of polymyositis, C protein-induced myositis (CIM). Methods: The susceptibility of mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice) to CIM was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/Wv mice to CIM was also evaluated. Results: W/Wv mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The infiltration of macrophages but not of CD8+ T cells in the skeletal muscle was attenuated in CIM of W/Wv mice. The expression of monocyte chemotactic protein-1 (MCP-1) in skeletal muscle was reduced in W/Wv mice. Vascular permeability in skeletal muscle was elevated in WT mice but not in W/Wv mice upon CIM induction. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/Wv mice. Conclusion: Mast cells play critical roles in the development of CIM.
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Sotiriou, V., Y. Huang, S. Ahmed, H. Isaksson, and NC Nowlan. "Prenatal murine skeletogenesis partially recovers from absent skeletal muscle as development progresses." European Cells and Materials 44 (November 8, 2022): 115–32. http://dx.doi.org/10.22203/ecm.v044a08.
Повний текст джерелаАнотація:
Skeletal muscle contractions are critical for normal skeletal growth and morphogenesis but it is unclear how the detrimental effects of absent muscle on the bones and joints change over time. Joint shape and cavitation as well as rudiment length and mineralisation were assessed in multiple rudiments at two developmental stages [Theiler stage (TS)24 and TS27] in the splotch-delayed “muscle-less limb” mouse model and littermate controls. Chondrocyte morphology was quantified in 3D in the distal humerus at the same stages. As development progressed, the effects of absent muscle on all parameters except for cavitation become less severe. All major joints in muscle-less limbs were abnormally shaped at TS24, while, by TS27, most muscle-less limb joint shapes were normal or nearly normal. In contrast, any joints that were fused at TS24 did not cavitate by TS27. At TS24, chondrocytes in the distal humerus were significantly smaller in the muscle-less limbs than in controls, while by TS27, chondrocyte volume was similar between the two groups, offering a cell-level mechanism for the partial recovery in shape of muscle-less limbs. Mineralisation showed the most pronounced changes over gestation. At TS24, all muscle-less rudiments studied had less mineralisation than the controls, while at TS27, muscle-less limb rudiments had mineralisation extents equivalent to controls. In conclusion, the effects of muscle absence on prenatal murine skeletogenesis reduced in severity over gestation. Understanding how mammalian bones and joints continue to develop in an environment with abnormal fetal movements provides insights into conditions including hip dysplasia and arthrogryposis.
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Khavandgar, Zohreh, Christophe Poirier, Christopher J. Clarke, Jingjing Li, Nicholas Wang, Marc D. McKee, Yusuf A. Hannun, and Monzur Murshed. "A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization." Journal of Cell Biology 194, no. 2 (July 25, 2011): 277–89. http://dx.doi.org/10.1083/jcb.201102051.
Повний текст джерелаАнотація:
A deletion mutation called fro (fragilitas ossium) in the murine Smpd3 (sphingomyelin phosphodiesterase 3) gene leads to a severe skeletal dysplasia. Smpd3 encodes a neutral sphingomyelinase (nSMase2), which cleaves sphingomyelin to generate bioactive lipid metabolites. We examined endochondral ossification in embryonic day 15.5 fro/fro mouse embryos and observed impaired apoptosis of hypertrophic chondrocytes and severely undermineralized cortical bones in the developing skeleton. In a recent study, it was suggested that nSMase2 activity in the brain regulates skeletal development through endocrine factors. However, we detected Smpd3 expression in both embryonic and postnatal skeletal tissues in wild-type mice. To investigate whether nSMase2 plays a cell-autonomous role in these tissues, we examined the in vitro mineralization properties of fro/fro osteoblast cultures. fro/fro cultures mineralized less than the control osteoblast cultures. We next generated fro/fro;Col1a1-Smpd3 mice, in which osteoblast-specific expression of Smpd3 corrected the bone abnormalities observed in fro/fro embryos without affecting the cartilage phenotype. Our data suggest tissue-specific roles for nSMase2 in skeletal tissues.
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Vanyai, Hannah K., Fabrice Prin, Oriane Guillermin, Bishara Marzook, Stefan Boeing, Alexander Howson, Rebecca E. Saunders, et al. "Control of skeletal morphogenesis by the Hippo-YAP/TAZ pathway." Development 147, no. 21 (September 29, 2020): dev187187. http://dx.doi.org/10.1242/dev.187187.
Повний текст джерелаАнотація:
ABSTRACTThe Hippo-YAP/TAZ pathway is an important regulator of tissue growth, but can also control cell fate or tissue morphogenesis. Here, we investigate the function of the Hippo pathway during the development of cartilage, which forms the majority of the skeleton. Previously, YAP was proposed to inhibit skeletal size by repressing chondrocyte proliferation and differentiation. We find that, in vitro, Yap/Taz double knockout impairs murine chondrocyte proliferation, whereas constitutively nuclear nls-YAP5SA accelerates proliferation, in line with the canonical role of this pathway in most tissues. However, in vivo, cartilage-specific knockout of Yap/Taz does not prevent chondrocyte proliferation, differentiation or skeletal growth, but rather results in various skeletal deformities including cleft palate. Cartilage-specific expression of nls-YAP5SA or knockout of Lats1/2 do not increase cartilage growth, but instead lead to catastrophic malformations resembling chondrodysplasia or achondrogenesis. Physiological YAP target genes in cartilage include Ctgf, Cyr61 and several matrix remodelling enzymes. Thus, YAP/TAZ activity controls chondrocyte proliferation in vitro, possibly reflecting a regenerative response, but is dispensable for chondrocyte proliferation in vivo, and instead functions to control cartilage morphogenesis via regulation of the extracellular matrix.
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Tribioli, C., and T. Lufkin. "The murine Bapx1 homeobox gene plays a critical role in embryonic development of the axial skeleton and spleen." Development 126, no. 24 (December 15, 1999): 5699–711. http://dx.doi.org/10.1242/dev.126.24.5699.
Повний текст джерелаАнотація:
Our previous studies in both mouse and human identified the Bapx1 homeobox gene, a member of the NK gene family, as one of the earliest markers for prechondrogenic cells that will subsequently undergo mesenchymal condensation, cartilage production and, finally, endochondral bone formation. In addition, Bapx1 is an early developmental marker for splanchnic mesoderm, consistent with a role in visceral mesoderm specification, a function performed by its homologue bagpipe, in Drosophila. The human homologue of Bapx1 has been identified and mapped to 4p16.1, a region containing loci for several skeletal diseases. Bapx1 null mice are affected by a perinatal lethal skeletal dysplasia and asplenia, with severe malformation or absence of specific bones of the vertebral column and cranial bones of mesodermal origin, with the most severely affected skeletal elements corresponding to ventral structures associated with the notochord. We provide evidence that the failure of the formation of skeletal elements in Bapx1 null embryos is a consequence of a failure of cartilage development, as demonstrated by downregulation of several molecular markers required for normal chondroblast differentiation (α 1(II) collagen, Fgfr3, Osf2, Indian hedgehog, Sox9), as well as a chondrocyte-specific alpha1 (II) collagen-lacZ transgene. The cartilage defects are correlated with failed differentiation of the sclerotome at the time when these cells are normally initiating chondrogenesis. Loss of Bapx1 is accompanied by an increase in apoptotic cell death in affected tissues, although cell cycling rates are unaltered.
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Iqbal, Aqsa, Ulrike May, Stuart N. Prince, Tero A. H. Järvinen та Ahlke Heydemann. "Systemically Administered Homing Peptide Targets Dystrophic Lesions and Delivers Transforming Growth Factor-β (TGFβ) Inhibitor to Attenuate Murine Muscular Dystrophy Pathology". Pharmaceutics 13, № 9 (18 вересня 2021): 1506. http://dx.doi.org/10.3390/pharmaceutics13091506.
Повний текст джерелаАнотація:
Muscular dystrophy is a progressively worsening and lethal disease, where accumulation of functionality-impairing fibrosis plays a key pathogenic role. Transforming growth factor-β1 (TGFβ1) is a central signaling molecule in the development of fibrosis in muscular dystrophic humans and mice. Inhibition of TGFβ1 has proven beneficial in mouse models of muscular dystrophy, but the global strategies of TGFβ1 inhibition produce significant detrimental side effects. Here, we investigated whether murine muscular dystrophy lesion-specific inhibition of TGFβ1 signaling by the targeted delivery of therapeutic decorin (a natural TGFβ inhibitor) by a vascular homing peptide CAR (CARSKNKDC) would reduce skeletal muscle fibrosis and pathology and increase functional characteristics of skeletal muscle. We demonstrate that CAR peptide homes to dystrophic lesions with specificity in two muscular dystrophy models. Recombinant fusion protein consisting of CAR peptide and decorin homes selectively to sites of skeletal muscle damage in mdxDBA2/J and gamma-sarcoglycan deficient DBA2/J mice. This targeted delivery reduced TGFβ1 signaling as demonstrated by reduced nuclear pSMAD staining. Three weeks of targeted decorin treatment decreased both membrane permeability and fibrosis and improved skeletal muscle function in comparison to control treatments in the mdxD2 mice. These results show that selective delivery of decorin to the sites of skeletal muscle damage attenuates the progression of murine muscular dystrophy.
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Abe, Makoto, Naoya Saeki, Yuki Ikeda, and Shinsuke Ohba. "Kruppel-like Factors in Skeletal Physiology and Pathologies." International Journal of Molecular Sciences 23, no. 23 (December 2, 2022): 15174. http://dx.doi.org/10.3390/ijms232315174.
Повний текст джерелаАнотація:
Kruppel-like factors (KLFs) belong to a large group of zinc finger-containing transcription factors with amino acid sequences resembling the Drosophila gap gene Krüppel. Since the first report of molecular cloning of the KLF family gene, the number of KLFs has increased rapidly. Currently, 17 murine and human KLFs are known to play crucial roles in the regulation of transcription, cell proliferation, cellular differentiation, stem cell maintenance, and tissue and organ pathogenesis. Recent evidence has shown that many KLF family molecules affect skeletal cells and regulate their differentiation and function. This review summarizes the current understanding of the unique roles of each KLF in skeletal cells during normal development and skeletal pathologies.
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Egeblad, Mikala, H. C. Jennifer Shen, Danielle J. Behonick, Lisa Wilmes, Alexandra Eichten, Lidiya V. Korets, Farrah Kheradmand, Zena Werb, and Lisa M. Coussens. "Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development." Developmental Dynamics 236, no. 6 (2007): 1683–93. http://dx.doi.org/10.1002/dvdy.21159.
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Egeblad, Mikala, H. C. Jennifer Shen, Danielle J. Behonick, Lisa Wilmes, Alexandra Eichten, Lidiya V. Korets, Farrah Kheradmand, Zena Werb, and Lisa M. Coussens. "Type I collagen is a genetic modifier of matrix metalloproteinase 2 in murine skeletal development." Developmental Dynamics 236, no. 8 (2007): spc1. http://dx.doi.org/10.1002/dvdy.21288.
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Cifuentes-Diaz, Carmen, Tony Frugier, Francesco D. Tiziano, Emmanuelle Lacène, Natacha Roblot, Vandana Joshi, Marie Helene Moreau, and Judith Melki. "Deletion of Murine SMN Exon 7 Directed to Skeletal Muscle Leads to Severe Muscular Dystrophy." Journal of Cell Biology 152, no. 5 (March 5, 2001): 1107–14. http://dx.doi.org/10.1083/jcb.152.5.1107.
Повний текст джерелаАнотація:
Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons of the spinal cord associated with muscle paralysis and caused by mutations of the survival motor neuron gene (SMN). To determine whether SMN gene defect in skeletal muscle might have a role in SMA pathogenesis, deletion of murine SMN exon 7, the most frequent mutation found in SMA, has been restricted to skeletal muscle by using the Cre-loxP system. Mutant mice display ongoing muscle necrosis with a dystrophic phenotype leading to muscle paralysis and death. The dystrophic phenotype is associated with elevated levels of creatine kinase activity, Evans blue dye uptake into muscle fibers, reduced amount of dystrophin and upregulation of utrophin expression suggesting a destabilization of the sarcolemma components. The mutant mice will be a valuable model for elucidating the underlying mechanism. Moreover, our results suggest a primary involvement of skeletal muscle in human SMA, which may contribute to motor defect in addition to muscle denervation caused by the motor neuron degeneration. These data may have important implications for the development of therapeutic strategies in SMA.
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Nordqvist, J., M. K. Lagerquist, L. Grahnemo, A. Koskela, U. Islander, and H. Carlsten. "Osteoporosis in a murine model of postmenopausal lupus." Lupus 29, no. 1 (December 11, 2019): 58–66. http://dx.doi.org/10.1177/0961203319893759.
Повний текст джерелаАнотація:
Background/objective Postmenopausal women with systemic lupus erythematosus have an increased risk of osteoporosis and associated fractures. Their increased osteoporosis risk is probably caused by a high level of inflammation, use of glucocorticoids, impaired kidney function, and early menopause as these are known risk factors for osteoporosis. Due to these risk factors and the lack of safe and effective treatments, new therapies for the treatment of osteoporosis in this group of patients are needed. Ovariectomized MRL/ lpr mice constitute a well-established model for studies of postmenopausal systemic lupus erythematosus; however, it is not clear to what extent this experimental model is associated with the development of osteoporosis. Thus, the aim of this study was to characterize the skeleton of ovariectomized MRL/ lpr mice to determine the suitability of this model in studies of prospective new therapies for osteoporosis in postmenopausal systemic lupus erythematosus patients. Methods Skeletal parameters were measured in MRL/ lpr mice and MRL/++ control mice, using peripheral quantitative computed tomography, high-resolution micro-computed tomography and biomechanical analyses. mRNA expression of bone-remodeling markers was measured by quantitative polymerase chain reaction and serological markers of lupus disease were evaluated using ELISA. Results Total bone mineral density was reduced in MRL/ lpr mice compared with MRL/++ mice and MRL/ lpr mice had reduced cortical and trabecular bone thickness compared with MRL/++ mice. In line with the low bone mass of MRL/ lpr mice, gene expression analysis of cortical bone from these mice indicated an increased osteoclast activity as well as a decreased osteoblastogenesis and osteoblast activity, compared with MRL/++ mice. Conclusion Ovariectomized MRL/ lpr mice constitute a valuable experimental model for studies of osteoporosis development in postmenopausal systemic lupus erythematosus and this model is thus suitable for future studies of osteoporosis treatment in systemic lupus erythematosus.
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Bies, Roger D., Stephanie F. Phelps, M. Dolores Cortez, Robert Roberts, C. Thomas Caskey, and Jeffrey S. Chamberlain. "Human and murine dystrophin mRNA transcripts are differentially expressed during skeletal muscle, heart, and brain development." Nucleic Acids Research 20, no. 7 (1992): 1725–31. http://dx.doi.org/10.1093/nar/20.7.1725.
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Robinson, Shawn W., Peter W. Cho, Hyam I. Levitsky, Jean L. Olson, Ralph H. Hruban, Michael A. Acker, and Paul D. Kessler. "Arterial Delivery of Genetically Labelled Skeletal Myoblasts to the Murine Heart: Long-Term Survival and Phenotypic Modification of Implanted Myoblasts." Cell Transplantation 5, no. 1 (January 1996): 77–91. http://dx.doi.org/10.1177/096368979600500113.
Повний текст джерелаАнотація:
The ability to replace damaged myocardial tissue with new striated muscle would constitute a major advance in the treatment of diseases that irreversibly injure cardiac muscle cells. The creation of focal grafts of skeletal muscle has been reported following the intramural injection of skeletal myoblasts into both normal and injured myocardium. The goals of this study were to determine whether skeletal myoblast-derived cells can be engrafted into the murine heart following arterial delivery. The murine heart was seeded with genetically labeled C2C12 myoblasts introduced into the arterial circulation of the heart via a transventricular injection. A transventricular injection provided access to the coronary and systemic circulations. Implanted cells were characterized using histochemical staining for β-galactosidase, immunofluorescent staining for muscle-specific antigens, and electron microscopy. Initially the injected cells were observed entrapped in myocardial capillaries. One week after injection myoblasts were present in the myocardial interstitium and were largely absent from the myocardial capillary bed. Implanted cells underwent myogenic development, characterized by the expression of a fast-twitch skeletal muscle sarco-endoplasmic reticulum calcium ATPase (SERCA1) and formation of myofilaments. Four months following injection myoblast-derived cells began to express a slow-twitch/cardiac protein, phospholamban, that is normally not expressed by C2C12 cells in vitro. Most surprisingly, regions of close apposition between LacZ labeled cells and native cardiomyocytes contained structures that resembled desmosomes, fascia adherens junctions, and gap junctions. The cardiac gap junction protein, connexin43, was localized to some of the interfaces between implanted cells and cardiomyocytes. Collectively, these findings suggest that arterially delivered myoblasts can be engrafted into the heart, and that prolonged residence in the myocardium may alter the phenotype of these skeletal muscle-derived cells. Further studies are necessary to determine whether arterial delivery of skeletal myoblasts can be developed as treatment for myocardial dysfunction.
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Quessada, Cyril, Alexandra Bouscary, Frédérique René, Cristiana Valle, Alberto Ferri, Shyuan T. Ngo, and Jean-Philippe Loeffler. "Skeletal Muscle Metabolism: Origin or Prognostic Factor for Amyotrophic Lateral Sclerosis (ALS) Development?" Cells 10, no. 6 (June 9, 2021): 1449. http://dx.doi.org/10.3390/cells10061449.
Повний текст джерелаАнотація:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.
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Alfieri, Christina M., Heather J. Evans-Anderson, and Katherine E. Yutzey. "Developmental regulation of the mouse IGF-I exon 1 promoter region by calcineurin activation of NFAT in skeletal muscle." American Journal of Physiology-Cell Physiology 292, no. 5 (May 2007): C1887—C1894. http://dx.doi.org/10.1152/ajpcell.00506.2006.
Повний текст джерелаАнотація:
Skeletal muscle development and growth are regulated through multiple signaling pathways that include insulin-like growth factor I (IGF-I) and calcineurin activation of nuclear factor of activated T cell (NFAT) transcription factors. The developmental regulation and molecular mechanisms that control IGF-I gene expression in murine embryos and in differentiating C2C12 skeletal myocytes were examined. IGF-I is expressed in developing skeletal muscle, and its embryonic expression is significantly reduced in embryos lacking both NFATc3 and NFATc4. During development, the IGF-I exon 1 promoter is active in multiple organ systems, including skeletal muscle, whereas the alternative exon 2 promoter is expressed predominantly in the liver. The IGF-I exon 1 promoter flanking sequence includes two highly conserved regions that contain NFAT consensus binding sequences. One of these conserved regions contains a calcineurin/NFAT-responsive regulatory region that is preferentially activated by NFATc3 in C2C12 skeletal muscle cells and NIH3T3 fibroblasts. This NFAT-responsive region contains three clustered NFAT consensus binding sequences, and mutagenesis experiments demonstrated the requirement for two of these in calcineurin or NFATc3 responsiveness. Chromatin immunoprecipitation analyses demonstrated that endogenous IGF-I genomic sequences containing these conserved NFAT binding sequences interact preferentially with NFATc3 in C2C12 cells. Together, these experiments demonstrated that a NFAT-rich regulatory element in the IGF-I exon 1 promoter flanking region is responsive to calcineurin signaling and NFAT activation in skeletal muscle cells. The identification of a calcineurin/NFAT-responsive element in the IGF-I gene represents a potential mechanism of intersection of these signaling pathways in the control of muscle development and homeostasis.
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Martens, Helge, Imke Hennies, Maike Getwan, Anne Christians, Anna-Carina Weiss, Frank Brand, Ann Christin Gjerstad, et al. "Rare heterozygous GDF6 variants in patients with renal anomalies." European Journal of Human Genetics 28, no. 12 (July 31, 2020): 1681–93. http://dx.doi.org/10.1038/s41431-020-0678-9.
Повний текст джерелаАнотація:
AbstractAlthough over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.
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Fahim, M. A., M. Y. Hasan, and W. B. Alshuaib. "Early morphological remodeling of neuromuscular junction in a murine model of diabetes." Journal of Applied Physiology 89, no. 6 (December 1, 2000): 2235–40. http://dx.doi.org/10.1152/jappl.2000.89.6.2235.
Повний текст джерелаАнотація:
Although skeletal muscle weakness is documented in diabetes, the time course for its development is not established. The present study examined the dorsiflexor muscle from animals that had been diabetic for 2 wk. Adult male c57BL mice were injected once with streptozotocin (STZ) to induce diabetes (60 mg/kg ip). Two weeks later, resting membrane potential and miniature end-plate potentials were recorded, and electron microscopy was utilized for ultrastructural evaluations. After STZ-induced diabetes, both resting membrane potential and miniature end-plate potentials were reduced. Nerve terminals showed less synaptic vesicles and had degenerated mitochondria. Furthermore, in the intramuscular nerves, disorganization of microtubules and neurofilaments was evidenced. Myelin-like figures were present in intramuscular nerves, neuromuscular junctions, and muscle fibers. At the muscle level, mitochondria were swollen, with disorganization of their cristae, disruption of T tubules, and myofibers with more deposition of glycogen granules. The present results revealed early STZ-induced nerve and muscle alterations. Observed ultrastructural modifications resemble those of motoneuron disorders and aging processes. These changes are possibly related to alterations in Ca2+ mobilization across muscle membrane. Other mechanisms such as free radical-mediated actions may also be implicated in STZ-induced effects on skeletal muscle.
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Oest, Megan E., Jeryl C. Jones, Cindy Hatfield, and M. Renee Prater. "Micro-CT evaluation of murine fetal skeletal development yields greater morphometric precision over traditional clear-staining methods." Birth Defects Research Part B: Developmental and Reproductive Toxicology 83, no. 6 (December 2008): 582–89. http://dx.doi.org/10.1002/bdrb.20177.
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Zhang, Chenyang, Shuai Zhang, and Yao Sun. "Expression of IFT140 During Bone Development." Journal of Histochemistry & Cytochemistry 67, no. 10 (June 25, 2019): 723–34. http://dx.doi.org/10.1369/0022155419859357.
Повний текст джерелаАнотація:
Primary cilia, hair-like organelles projecting from the surface of cells, are critical for sensing extracellular stimuli and transmitting molecular signals that regulate cell functions. During bone development, cell cilia are found in several types of cells, but their roles require further investigation. Intraflagellar transport (IFT) is essential for the formation and maintenance of most eukaryotic cilia. IFT140 is a core protein of the IFT-A complex. Mutations in IFT140 have been associated with cases of skeletal ciliopathies. In this study, we examined the expression of IFT140 during bone development. The results showed that, compared with many soft tissues, Ift140 (mRNA level) was highly expressed in bone. Moreover, its expression level was downregulated in the long bones of murine osteoporosis models. At the histological level, IFT140 was characteristically expressed in osteoblasts and chondrocytes at representative stages of bone development, and its expression level in these two types of cells was observed in two waves. These findings suggest that IFT140 may play an important role in the process of chondrogenic and osteogenic differentiation during bone development.
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Ma, Yue, Manoharee Samaraweera, Sandra Cooke-Hubley, Beth J. Kirby, Andrew C. Karaplis, Beate Lanske, and Christopher S. Kovacs. "Neither Absence Nor Excess of FGF23 Disturbs Murine Fetal-Placental Phosphorus Homeostasis or Prenatal Skeletal Development and Mineralization." Endocrinology 155, no. 5 (May 1, 2014): 1596–605. http://dx.doi.org/10.1210/en.2013-2061.
Повний текст джерелаАнотація:
Fibroblast growth factor-23 (FGF23) controls serum phosphorus largely through actions on the kidneys to excrete phosphorus and reduce calcitriol. Although these actions are well established in adults and children, the role that FGF23 plays in regulating fetal phosphorus metabolism has not been previously studied. We used several mouse models to study the effect of endogenous deficiency or excess of FGF23 on fetal phosphorus metabolism. We found that intact FGF23 does not cross the placenta from mother to fetus, but wild-type fetuses normally have intact FGF23 levels that approximately equal the maternal level. Deletion of Fgf23 or 7.8-fold higher serum FGF23 levels did not disturb any parameter of fetal mineral homeostasis, including serum and amniotic fluid phosphorus, skeletal morphology, skeletal mineral content, and placental phosphorus transport. Placentas and fetal kidneys abundantly express FGF23 target genes. Cyp24a1 was significantly reduced in Fgf23 null kidneys and was significantly increased in Phex null placentas and fetal kidneys. Phex null kidneys also showed reduced expression of Klotho. However, these changes in gene expression did not disturb any physiological parameter related to phosphorus. A 50% reduction in FGF23 also failed to affect renal phosphorus excretion into amniotic fluid when either PTH or the vitamin D receptor were absent. In conclusion, FGF23 is not an important regulator of fetal phosphorous metabolism. The active delivery of phosphorus across the placenta does not require FGF23, and that process overrides any effects that absence or excess of FGF23 might otherwise have on phosphate handling by the fetal kidneys.
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Carter, W. O., C. Bull, E. Bortolon, L. Yang, G. J. Jesmok, and R. H. Gundel. "A murine skeletal muscle ischemia-reperfusion injury model: differential pathology in BALB/c and DBA/2N mice." Journal of Applied Physiology 85, no. 5 (November 1, 1998): 1676–83. http://dx.doi.org/10.1152/jappl.1998.85.5.1676.
Повний текст джерелаАнотація:
Ischemia-reperfusion injuries can occur with diseases such as myocardial infarction and stroke and during surgical procedures such as organ transplantation and correction of aortic aneurysms. We developed a murine model to mimic abdominal aortic aneurysm repair with cross-clamping of the aorta distal to the renal artery. After model development, we compared the normal complement BALB/c mouse with the C5-deficient DBA/2N mouse. To assess quantitative differences, we measured neuromuscular function up to 72 h after ischemia with a subjective clinical scoring system, as well as plasma chemistries, hematology, and histopathology. There were significant increases in clinical scores and creatine phosphokinase, lactate dehydrogenase, and muscle histopathology scores in BALB/c mice compared with those in DBA/2N mice and sham-surgery mice. Muscle histopathology scores of the cranial tibialis and quadriceps correlated well with clinical signs, creatine phosphokinase, and lactate dehydrogenase, and indicated the greatest pathology in these muscle groups. We developed a murine model of skeletal muscle ischemia-reperfusion injury that can utilize the benefits of murine genetic and transgenic models to assess therapeutic principles of this model. Additionally, we have shown a significant reduction in clinical signs, plasma muscle enzyme concentrations, and muscle pathology in the C5-deficient DBA/2N mouse in this model.
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Lima, Maria, Shuichi Sato, Reilly T. Enos, John W. Baynes, and James A. Carson. "Development of an UPLC mass spectrometry method for measurement of myofibrillar protein synthesis: application to analysis of murine muscles during cancer cachexia." Journal of Applied Physiology 114, no. 6 (March 15, 2013): 824–28. http://dx.doi.org/10.1152/japplphysiol.01141.2012.
Повний текст джерелаАнотація:
Cachexia, characterized by skeletal muscle mass loss, is a major contributory factor to patient morbidity and mortality during cancer. However, there are no reports on the rate of myofibrillar protein synthesis (MPS) in skeletal muscles that vary in primary metabolic phenotype during cachexia, in large part because of the small-size muscles and regional differences in larger muscles in the mouse. Here, we describe a sensitive method for measurement of MPS and its application to analysis of MPS in specific muscles of mice with ( Apc Min/+) and without (C57BL/6) cancer cachexia. Mice were injected with a loading dose of deuterated phenylalanine (D5F), and myofibrillar proteins were extracted from skeletal muscles at 30 min. The relative concentrations of D5F and naturally occurring phenylalanine (F) in the myofibrillar proteins and the amino acid pool were quantified by ultra-performance liquid chromatograph (UPLC) mass spectrometry (MS). The rate of MPS was determined from D5F-to-F ratio in the protein fraction compared with the amino acid pool. The rate of MPS, measured in 2–5 mg of muscle protein, was reduced by up to 65% with cachexia in the soleus, plantaris, diaphragm, and oxidative and glycolytic regions of the gastrocnemius. The rate of MPS was significantly higher in the oxidative vs. glycolytic gastrocnemius muscle. A sufficiently sensitive UPLC MS method requiring a very small amount of muscle has been developed to measure the rate of MPS in various mouse muscles. This method should be useful for studies in other animal models for quantifying effects of cancer and anti-cancer therapies on protein synthesis in cachexia, and particularly for analysis of sequential muscle biopsies in a wide range of animal and human studies.
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Walsh, F. S., and A. J. Celeste. "Myostatin: a modulator of skeletal-muscle stem cells." Biochemical Society Transactions 33, no. 6 (October 26, 2005): 1513–17. http://dx.doi.org/10.1042/bst0331513.
Повний текст джерелаАнотація:
Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-β (transforming growth factor-β) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in ‘double muscled’ cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle development. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular dystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis.
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Core, N., S. Bel, S. J. Gaunt, M. Aurrand-Lions, J. Pearce, A. Fisher, and M. Djabali. "Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice." Development 124, no. 3 (February 1, 1997): 721–29. http://dx.doi.org/10.1242/dev.124.3.721.
Повний текст джерелаАнотація:
In Drosophila, the trithorax-group and the Polycomb-group genes are necessary to maintain the expression of the homeobox genes in the appropriate segments. Loss-of-function mutations in those groups of genes lead to misexpression of the homeotic genes resulting in segmental homeotic transformations. Recently, mouse homologues of the Polycomb-group genes were identified including M33, the murine counterpart of Polycomb. In this report, M33 was targeted in mice by homologous recombination in embryonic stem (ES) cells to assess its function during development. Homozygous M33 (−/−) mice show greatly retarded growth, homeotic transformations of the axial skeleton, sternal and limb malformations and a failure to expand in vitro of several cell types including lymphocytes and fibroblasts. In addition, M33 null mutant mice show an aggravation of the skeletal malformations when treated to RA at embryonic day 7.5, leading to the hypothesis that, during development, the M33 gene might play a role in defining access to retinoic acid response elements localised in the regulatory regions of several Hox genes.
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Ding, Mengmeng, Li Jin, Lin Xie, So Hyun Park, Yixin Tong, Di Wu, A. Bobby Chhabra, Zheng Fu, and Xudong Li. "A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development." Calcified Tissue International 102, no. 3 (November 2, 2017): 348–57. http://dx.doi.org/10.1007/s00223-017-0355-3.
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Kawanishi, C. Y., P. Hartig, K. L. Bobseine, J. Schmid, M. Cardon, G. Massenburg, and N. Chernoff. "Axial skeletal and hox expression domain alterations induced by retinoic acid, valproic acid, and bromoxynil during murine development." Journal of Biochemical and Molecular Toxicology 17, no. 6 (December 2003): 346–56. http://dx.doi.org/10.1002/jbt.10098.
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Sciandra, Francesca, Maria Giulia Bigotti, Bruno Giardina, Manuela Bozzi, and Andrea Brancaccio. "Genetic Engineering of Dystroglycan in Animal Models of Muscular Dystrophy." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/635792.
Повний текст джерелаАнотація:
In skeletal muscle, dystroglycan (DG) is the central component of the dystrophin-glycoprotein complex (DGC), a multimeric protein complex that ensures a strong mechanical link between the extracellular matrix and the cytoskeleton. Several muscular dystrophies arise from mutations hitting most of the components of the DGC. Mutations within the DG gene (DAG1) have been recently associated with two forms of muscular dystrophy, one displaying a milder and one a more severe phenotype. This review focuses specifically on the animal (murine and others) model systems that have been developed with the aim of directly engineeringDAG1in order to study the DG function in skeletal muscle as well as in other tissues. In the last years, conditional animal models overcoming the embryonic lethality of the DG knock-out in mouse have been generated and helped clarifying the crucial role of DG in skeletal muscle, while an increasing number of studies on knock-in mice are aimed at understanding the contribution of single amino acids to the stability of DG and to the possible development of muscular dystrophy.
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Hoffmann, Andrea, Stefan Czichos, Christian Kaps, Dietmar Bächner, Hubert Mayer, Yoram Zilberman, Gadi Turgeman, Gadi Pelled, Gerhard Gross, and Dan Gazit. "The T-box transcription factor Brachyury mediates cartilage development in mesenchymal stem cell line C3H10T1/2." Journal of Cell Science 115, no. 4 (February 15, 2002): 769–81. http://dx.doi.org/10.1242/jcs.115.4.769.
Повний текст джерелаАнотація:
The BMP2-dependent onset of osteo/chondrogenic differentiation in the acknowledged pluripotent murine mesenchymal stem cell line (C3H10T1/2) is accompanied by the immediate upregulation of Fibroblast Growth Factor Receptor 3 (FGFR3) and a delayed response by FGFR2. Forced expression of FGFR3 in C3H10T1/2 is sufficient for chondrogenic differentiation, indicating an important role for FGF-signaling during the manifestation of the chondrogenic lineage in this cell line. Screening for transcription factors exhibiting a chondrogenic capacity in C3H10T1/2 indentified that the T-box containing transcription factor Brachyury is upregulated by FGFR3-mediated signaling. Forced expression of Brachyury in C3H10T1/2 was sufficient for differentiation into the chondrogenic lineage in vitro and in vivo after transplantation into muscle. A dominant-negative variant of Brachyury, consisting of its DNA-binding domain (T-box), interferes with BMP2-mediated cartilage formation. These studies indicate that BMP-initiated FGF-signaling induces a novel type of transcription factor for the onset of chondrogenesis in a mesenchymal stem cell line. A potential role for this T-box factor in skeletogenesis is further delineated from its expression profile in various skeletal elements such as intervertebral disks and the limb bud at late stages (18.5 d.p.c.) of murine embryonic development.
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Abdel-Raouf, Khaled M. A., Rachid Rezgui, Cesare Stefanini, Jeremy C. M. Teo, and Nicolas Christoforou. "Transdifferentiation of Human Fibroblasts into Skeletal Muscle Cells: Optimization and Assembly into Engineered Tissue Constructs through Biological Ligands." Biology 10, no. 6 (June 16, 2021): 539. http://dx.doi.org/10.3390/biology10060539.
Повний текст джерелаАнотація:
The development of robust skeletal muscle models has been challenging due to the partial recapitulation of human physiology and architecture. Reliable and innovative 3D skeletal muscle models recently described offer an alternative that more accurately captures the in vivo environment but require an abundant cell source. Direct reprogramming or transdifferentiation has been considered as an alternative. Recent reports have provided evidence for significant improvements in the efficiency of derivation of human skeletal myotubes from human fibroblasts. Herein we aimed at improving the transdifferentiation process of human fibroblasts (tHFs), in addition to the differentiation of murine skeletal myoblasts (C2C12), and the differentiation of primary human skeletal myoblasts (HSkM). Differentiating or transdifferentiating cells were exposed to single or combinations of biological ligands, including Follistatin, GDF8, FGF2, GDF11, GDF15, hGH, TMSB4X, BMP4, BMP7, IL6, and TNF-α. These were selected for their critical roles in myogenesis and regeneration. C2C12 and tHFs displayed significant differentiation deficits when exposed to FGF2, BMP4, BMP7, and TNF-α, while proliferation was significantly enhanced by FGF2. When exposed to combinations of ligands, we observed consistent deficit differentiation when TNF-α was included. Finally, our direct reprogramming technique allowed for the assembly of elongated, cross-striated, and aligned tHFs within tissue-engineered 3D skeletal muscle constructs. In conclusion, we describe an efficient system to transdifferentiate human fibroblasts into myogenic cells and a platform for the generation of tissue-engineered constructs. Future directions will involve the evaluation of the functional characteristics of these engineered tissues.
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Renthal, Nora Edwards, Priyanka Nakka, John Baronas, Henry M. Kronenberg, and Joel N. Hirschhorn. "Specificity for the Epiphyseal Round Cell Layer is Significantly Associated With Height GWAS." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A685. http://dx.doi.org/10.1210/jendso/bvab048.1396.
Повний текст джерелаАнотація:
Abstract Human height is a model polygenic trait with thousands of height-related SNPs identified in GWAS to date. An important determinant of height is the proliferation and hypertrophy of growth plate chondrocytes during childhood long bone elongation. Connecting the expression of specific genes that affect skeletal biology to associated variants in GWAS remains a difficult challenge. To connect the genetics of height and growth plate gene expression, we studied the relationship between gene expression in the murine growth plate and common-variant associations from GWAS of height. To obtain gene expression data from the growth plate, we dissected three layers of murine tibial growth plates, extracted RNA from each layer, and measured expression using the Affymetrix GeneChip 430 3.0. For each gene, we derived a specificity score for each growth plate layer, and SNP-level p-values from a published GWAS of height (N~700000) were combined into gene-level p-values using MAGMA. We then used MAGMA to test for association between specificity of expression for each growth plate layer and the GWAS gene level p-values for height. We found that specificity for the round cell layer is significantly associated with height GWAS p-values (p = 8.5x10-9). This association remains when we condition on each of the other cell layers and on membership in a set of genes from OMIM that cause skeletal growth disorders (3.3x10-8 < p < 4.1x10-6). We replicated this result in a RNA-seq dataset of maturing chondrocytes sampled at three time points during development in vitro (days 3, 5, and 10): we found that z-scores for expression in the earliest two days of development are significantly associated with gene-level p-values from height GWAS (pDay3 = 1.2x10-21 and pDay5 = 2.0x10-20) and that this association remains after conditioning on the other timepoints and on the OMIM gene set (3.1x10-20 < pDay3 < 8.3x10-5; 3.7x10-19 < pDay5 < 0.002). We then performed pathway analysis of genes that are both highly specific to the round layer and highly significant in GWAS using Enrichr. Together, our results suggest that genes expressed in early chondrocyte development (the round cell layer) are particularly relevant to the contribution of growth plate-expressed genes to height. This conclusion both sheds light on the regulation of human skeletal growth and also helps prioritize relevant genes implicated from the height GWAS in skeletal biology.
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Mu, Xiaodong, Rashmi Agarwal, Daniel March, Adam Rothenberg, Clifford Voigt, Jessica Tebbets, Johnny Huard, and Kurt Weiss. "Notch Signaling Mediates Skeletal Muscle Atrophy in Cancer Cachexia Caused by Osteosarcoma." Sarcoma 2016 (2016): 1–12. http://dx.doi.org/10.1155/2016/3758162.
Повний текст джерелаАнотація:
Skeletal muscle atrophy in cancer cachexia is mediated by the interaction between muscle stem cells and various tumor factors. Although Notch signaling has been known as a key regulator of both cancer development and muscle stem cell activity, the potential involvement of Notch signaling in cancer cachexia and concomitant muscle atrophy has yet to be elucidated. The murine K7M2 osteosarcoma cell line was used to generate an orthotopic model of sarcoma-associated cachexia, and the role of Notch signaling was evaluated. Skeletal muscle atrophy was observed in the sarcoma-bearing mice, and Notch signaling was highly active in both tumor tissues and the atrophic skeletal muscles. Systemic inhibition of Notch signaling reduced muscle atrophy.In vitrococulture of osteosarcoma cells with muscle-derived stem cells (MDSCs) isolated from normal mice resulted in decreased myogenic potential of MDSCs, while the application of Notch inhibitor was able to rescue this repressed myogenic potential. We further observed that Notch-activating factors reside in the exosomes of osteosarcoma cells, which activate Notch signaling in MDSCs and subsequently repress myogenesis. Our results revealed that signaling between tumor and muscle via the Notch pathway may play an important role in mediating the skeletal muscle atrophy seen in cancer cachexia.
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Oliver, G., R. Wehr, N. A. Jenkins, N. G. Copeland, B. N. Cheyette, V. Hartenstein, S. L. Zipursky, and P. Gruss. "Homeobox genes and connective tissue patterning." Development 121, no. 3 (March 1, 1995): 693–705. http://dx.doi.org/10.1242/dev.121.3.693.
Повний текст джерелаАнотація:
In vertebrates, limb tendons are derived from cells that migrate from the lateral plate mesoderm during early development. While some of the developmental steps leading to the formation of these tissues are known, little is known about the molecular mechanisms controlling them. We have identified two murine homeobox-containing genes, Six 1 and Six 2, which are expressed in a complementary fashion during the development of limb tendons. Transcripts for both genes are found in different sets of phalangeal tendons. Six 1 and Six 2 also are expressed in skeletal and smooth muscle, respectively. These genes may participate in the patterning of the distal tendons of the limb phalanges by setting positional values along the limb axes.
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Chan, Yi-Sheng, Yong Li, William Foster, Takashi Horaguchi, George Somogyi, Freddie H. Fu, and Johnny Huard. "Antifibrotic effects of suramin in injured skeletal muscle after laceration." Journal of Applied Physiology 95, no. 2 (August 2003): 771–80. http://dx.doi.org/10.1152/japplphysiol.00915.2002.
Повний текст джерелаАнотація:
Muscle injuries are very common in traumatology and sports medicine. Although muscle tissue can regenerate postinjury, the healing process is slow and often incomplete; complete recovery after skeletal muscle injury is hindered by fibrosis. Our studies have shown that decreased fibrosis could improve muscle healing. Suramin has been found to inhibit transforming growth factor (TGF)-β1 expression by competitively binding to the growth factor receptor. We conducted a series of tests to determine the antifibrotic effects of suramin on muscle laceration injuries. Our results demonstrate that suramin (50 μg/ml) can effectively decrease fibroblast proliferation and fibrotic-protein expression (α-smooth muscle actin) in vitro. In vivo, direct injection of suramin (2.5 mg) into injured murine muscle resulted in effective inhibition of muscle fibrosis and enhanced muscle regeneration, which led to efficient functional muscle recovery. These results support our hypothesis that prevention of fibrosis could enhance muscle regeneration, thereby facilitating more efficient muscle healing. This study could significantly contribute to the development of strategies to promote efficient muscle healing and functional recovery.
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Takács, Anna C., Izabela J. Swierzy та Carsten G. K. Lüder. "Interferon-γ Restricts Toxoplasma gondii Development in Murine Skeletal Muscle Cells via Nitric Oxide Production and Immunity-Related GTPases". PLoS ONE 7, № 9 (14 вересня 2012): e45440. http://dx.doi.org/10.1371/journal.pone.0045440.
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Syed, Farhan A., Daniel G. Fraser, Thomas C. Spelsberg, Clifford J. Rosen, Andree Krust, Pierre Chambon, J. Larry Jameson, and Sundeep Khosla. "Effects of Loss of Classical Estrogen Response Element Signaling on Bone in Male Mice." Endocrinology 148, no. 4 (April 1, 2007): 1902–10. http://dx.doi.org/10.1210/en.2006-1165.
Повний текст джерелаАнотація:
The role of estrogen signaling in the male skeleton via estrogen receptor (ER)-α is now well established. ERα can elicit responses through either classical estrogen response elements (ERE) pathways or nonclassical, non-ERE pathways. In the present study, we examined the effects of either the attenuation or loss of classical ERα signaling on the murine male skeleton. To accomplish this, we crossed male mice heterozygous for a knock-in mutation [nonclassical ERα knock-in (NERKI)], which abolishes the ERE-mediated pathway with female heterozygous ERα knockout mice (ERα+/−) and studied the F1 generation ERα+/+, ERα+/−, ERα +/NERKI, and ERα−/NERKI male progeny longitudinally using bone density and histomorphometry. The only ERα allele present in ERα−/NERKI mice is incapable of classical ERE-mediated signaling, whereas the heterozygous ERα+/NERKI mice have both one intact ERα and one NERKI allele. As compared with ERα+/+ littermates (n = 10/genotype), male ERα+/NERKI and ERα−/NERKI mice displayed axial and appendicular skeletal osteopenia at 6, 12, 20, and 25 wk of age, as demonstrated by significant reductions in total bone mineral density (BMD) at representative sites (areal BMD by dual-energy x-ray absorptiometry at the lumbar vertebrae and femur and volumetric BMD by peripheral quantitative computed tomography at the tibia; P < 0.05–0.001 vs. ERα+/+). The observed osteopenia in these mice was evident in both trabecular and cortical bone compartments. However, these decreases were more severe in mice lacking classical ERα signaling (ERα−/NERKI mice), compared with mice in which one wild-type ERα allele was present (ERα+/NERKI mice). Collectively, these data demonstrate that classical ERα signaling is crucial for the development of the murine male skeleton.
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Gao, Xueqin, Ying Tang, Sarah Amra, Xuying Sun, Yan Cui, Haizi Cheng, Bing Wang, and Johnny Huard. "Systemic investigation of bone and muscle abnormalities in dystrophin/utrophin double knockout mice during postnatal development and the mechanisms." Human Molecular Genetics 28, no. 10 (January 28, 2019): 1738–51. http://dx.doi.org/10.1093/hmg/ddz012.
Повний текст джерелаАнотація:
Abstract The dystrophin−/−/utrophin−/−/ double knockout (dKO-Hom) mouse is a murine model of human Duchenne muscular dystrophy. This study investigated the bone and muscle abnormalities of dKO-Hom mouse and mechanisms. We collected bone and skeletal muscle samples from control mice and three muscular dystrophic mouse models at different ages and performed micro-computer tomography and histological analyses of both bone and skeletal muscle tissues. Serum receptor activator of nuclear factor kappa-Β ligand (RANKL) and sclerostin (SOST) levels, osteoclastogenesis and serum proteomics were also analyzed. Our results indicated that dKO-Hom mice developed skeletal muscle histopathologies by 5 days of age, whereas bone abnormalities developed at 4 weeks of age. Furthermore, our results indicated that the numbers of osteoblasts and osteoclasts were decreased in the proximal tibia and spine trabecular bone of dKO-Hom mice compared to wild-type (WT) mice, which correlated with a significant reduction in serum RANKL levels. The number of tibia cortical osteocytes also decreased, whereas serum SOST levels increased significantly in dKO-Hom mice than WT mice. Osteoblastic number was significantly lower, but osteoclast number increased, in the spine L6 of dKO-Hom mice than WT mice at 6 weeks of age, resulting in a decrease in bone formation and an increase in bone resorption. Serum proteomics results revealed abnormal proteome profiles in dKO-Hom mice compared to control mice. In conclusion, our study elucidated the timing of development of bone and muscle abnormalities. The bone abnormalities in dKO-Hom mice are correlated with lower serum RANKL and higher SOST levels that resulted in dysregulation of osteogenesis and osteoclastogenesis and bone loss.
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Lee, Eun Ju, Sibhghatulla Shaikh, Dukhwan Choi, Khurshid Ahmad, Mohammad Hassan Baig, Jeong Ho Lim, Yong-Ho Lee, et al. "Transthyretin Maintains Muscle Homeostasis through the Novel Shuttle Pathway of Thyroid Hormones during Myoblast Differentiation." Cells 8, no. 12 (December 4, 2019): 1565. http://dx.doi.org/10.3390/cells8121565.
Повний текст джерелаАнотація:
Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXRγ (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.
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Kleger, Alexander, Stefan Liebau, Qiong Lin, Götz von Wichert, and Thomas Seufferlein. "The Impact of Bioactive Lipids on Cardiovascular Development." Stem Cells International 2011 (2011): 1–13. http://dx.doi.org/10.4061/2011/916180.
Повний текст джерелаАнотація:
Lysophospholipids comprise a group of bioactive molecules with multiple biological functions. The cardinal members of this signalling molecule group are sphingosylphosphorylcholine (SPC), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P) which are, at least in part, homologous to each other. Bioactive lipids usually act via G-protein coupled receptors (GPCRs), but can also function as direct intracellular messengers. Recently, it became evident that bioactive lipids play a role during cellular differentiation development. SPC induces mesodermal differentiation of mouse ES cells and differentiation of promyelocytic leukemia cells, by a mechanism being critically dependent on MEK-ERK signalling. LPA stimulates the clonal expansion of neurospheres from neural stem/progenitor cells and induces c-fos via activation of mitogen- and stress-activated protein kinase 1 (MSK1) in ES cells. S1P acts on hematopoietic progenitor cells as a chemotactic factor and has also been found to be critical for cardiac and skeletal muscle regeneration. Furthermore, S1P promotes cardiogenesis and similarly activates Erk signalling in mouse ES cells. Interestingly, S1P may also act to maintain human stem cell pluripotency. Both LPA and S1P positively regulate the proliferative capacity of murine ES cells. In this paper we will focus on the differential and developmental impact of lysophospholipids on cardiovascular development.
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Raffa, Paolo, Maria Easler, Francesca Cecchinato, Beatrice Auletta, Valentina Scattolini, Silvia Perin, Mattia Francesco Maria Gerli, et al. "Decellularized Skeletal Muscles Support the Generation of In Vitro Neuromuscular Tissue Models." Applied Sciences 11, no. 20 (October 13, 2021): 9485. http://dx.doi.org/10.3390/app11209485.
Повний текст джерелаАнотація:
Decellularized skeletal muscle (dSkM) constructs have received much attention in recent years due to the versatility of their applications in vitro. In search of adequate in vitro models of the skeletal muscle tissue, the dSkM offers great advantages in terms of the preservation of native-tissue complexity, including three-dimensional organization, the presence of residual signaling molecules within the construct, and their myogenic and neurotrophic abilities. Here, we attempted to develop a 3D model of neuromuscular tissue. To do so, we repopulated rat dSkM with human primary myogenic cells along with murine fibroblasts and we coupled them with organotypic rat spinal cord samples. Such culture conditions not only maintained multiple cell type viability in a long-term experimental setup, but also resulted in functionally active construct capable of contraction. In addition, we have developed a customized culture system which enabled easy access, imaging, and analysis of in vitro engineered co-cultures. This work demonstrates the ability of dSkM to support the development of a contractile 3D in vitro model of neuromuscular tissue fit for long-term experimental evaluations.
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Yin, Qian, Li Tang, Kaimin Cai, Rong Tong, Rachel Sternberg, Xujuan Yang, Lawrence W. Dobrucki, et al. "Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis." Proceedings of the National Academy of Sciences 113, no. 32 (July 25, 2016): E4601—E4609. http://dx.doi.org/10.1073/pnas.1603316113.
Повний текст джерелаАнотація:
Malignant osteolysis associated with inoperable primary bone tumors and multifocal skeletal metastases remains a challenging clinical problem in cancer patients. Nanomedicine that is able to target and deliver therapeutic agents to diseased bone sites could potentially provide an effective treatment option for different types of skeletal cancers. Here, we report the development of polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam) for the targeted treatment of malignant skeletal tumors. In vivo biodistribution of radiolabeled targeted Pam-NPs demonstrated enhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. In a murine model of focal malignant osteolysis, Pam-functionalized, Doxo-loaded NPs (Pam-Doxo-NPs) significantly attenuated localized osteosarcoma (OS) progression compared with nontargeted Doxo-NPs. Importantly, we report on the first evaluation to our knowlege of Pam-Doxo-NPs in dogs with OS, which possess tumors of anatomic size and physiology comparable to those in humans. The repeat dosing of Pam-Doxo-NPs in dogs with naturally occurring OS indicated the therapeutic was well tolerated without hematologic, nonhematologic, and cardiac toxicities. By nuclear scintigraphy, the biodistribution of Pam-Doxo-NPs demonstrated malignant bone-targeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.
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Wanderling, Sherry, Birgitte B. Simen, Olga Ostrovsky, Noreen T. Ahmed, Shawn M. Vogen, Tali Gidalevitz, and Yair Argon. "GRP94 Is Essential for Mesoderm Induction and Muscle Development Because It Regulates Insulin-like Growth Factor Secretion." Molecular Biology of the Cell 18, no. 10 (October 2007): 3764–75. http://dx.doi.org/10.1091/mbc.e07-03-0275.
Повний текст джерелаАнотація:
Because only few of its client proteins are known, the physiological roles of the endoplasmic reticulum chaperone glucose-regulated protein 94 (GRP94) are poorly understood. Using targeted disruption of the murine GRP94 gene, we show that it has essential functions in embryonic development. grp94−/− embryos die on day 7 of gestation, fail to develop mesoderm, primitive streak, or proamniotic cavity. grp94−/− ES cells grow in culture and are capable of differentiation into cells representing all three germ layers. However, these cells do not differentiate into cardiac, smooth, or skeletal muscle. Differentiation cultures of mutant ES cells are deficient in secretion of insulin-like growth factor II and their defect can be complemented with exogenous insulin-like growth factors I or II. The data identify insulin-like growth factor II as one developmentally important protein whose production depends on the activity of GRP94. Keywords: chaperone/HSP90/Insulin-like growth factors/mouse development.
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Maor, G., Z. Laron, R. Eshet, and M. Silbermann. "The early postnatal development of the murine mandibular condyle is regulated by endogenous insulin-like growth factor-I." Journal of Endocrinology 137, no. 1 (April 1993): 21—NP. http://dx.doi.org/10.1677/joe.0.1370021.
Повний текст джерелаАнотація:
ABSTRACT Skeletal growth during the early postnatal period is thought to be GH-independent, and is probably regulated by intrinsic growth factors. We studied the involvement of locally produced insulin like growth factor-I (IGF-I) in the growth of the neonatal mandibular condyle. Immunofluorescence studies revealed intense staining with antibodies to IGF-I in the mandibular condyle of 2-day-old ICR mice. We have also shown that these mandibular condyles contain specific high-affinity binding sites (Kd = 0·157 nmol/l) for IGF-I (427 fmol/mg). Autoradiographical studies of iodinated IGF-I revealed that the distribution of the receptors for IGF-I was parallel to that of IGF-I production, mainly in the younger zones of the condyle, namely the chondroprogenitor and the chondroblast cell layers. Immunoinhibition of IGF-I resulted in an almost complete inhibition (−91%) of thymidine incorporation into DNA, as well as in marked degenerative changes in the morphological appearance of the condyle. Our studies support the hypothesis that early postnatal growth is dependent on the paracrine activity of endogenous GH-independent IGF-I. Journal of Endocrinology (1993) 137, 21–26
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He, Yongzheng, Karl Staser, Steven D. Rhodes, Xiaohua Wu, Ping Zhang, Shi Chen, and Feng-chun Yang. "Erk1 Plays Critical Role in Macrophage Development." Blood 118, no. 21 (November 18, 2011): 517. http://dx.doi.org/10.1182/blood.v118.21.517.517.
Повний текст джерелаАнотація:
Abstract Abstract 517 Extracellular signal-regulated kinase (ERK 1 and 2) are widely expressed and are involved in the regulation of meiosis, mitosis, and postmitotic functions in multiple cell lineages, including T cells, B cells and osteoblasts. Macrophages are capable of differentiating into osteoclasts, which resorb bone. Abnormal osteoclast development and functions underlie certain diseases, especially skeletal defects. Altered ERK1/2 signaling has been found in several genetic diseases with skeletal phenotypes, including Noonan syndrome, polycystic kidney disease and serious developmental disorders such as cardio-facio-cutaneous syndrome. These clinical findings suggest the importance of the ERK MAPK pathway in human skeletal development. In the present study, we examined the consequence of Erk1 and Erk2 disruption in modulating macrophage development in the murine system. We found that deletion of Erk1 reduced macrophage progenitor numbers. Erk1−/− bone marrow mononuclear cells (BMMNCs) had significant reduction in osteoclast formation as compared to wildtype BMMNCs. In addition, Erk1−/− macrophages; the osteoclast progenitors, had a two-three fold reduction in migration and a two-fold reduction in αv ß3 mediated adhesion as compared to WT macrophages as evaluated by transwell and adhesion assay, respectively. These in vitro data demonstrate that Erk1 positively regulates macrophage differentiation into osteoclasts. To evaluate the impact of deficiency of Erk1 in vivo, we examined bone mineral density and trabecular microarchitecture in the distal femoral metaphysis by dual-energy X-ray absorptiometry (DEXA) with a Lunar Piximus densitometer and a high-resolution desktop microcomputed tomography imaging system (μCT-20; Scanco Medical AG, Basserdorf, Switzerland), respectively. Erk1−/− mice displayed elevated bone mineral density and increased trabecular bone formation as compared to WT mice. Histomorphometric analysis indicated that the Erk1−/− femur had significant reduction in osteoclast numbers as determined by tartrate resistant acid phosphatase staining, an osteoclast specific staining, as compared to femur of wildtype and Erk2−/− mice. Most importantly, Erk1−/− plasma had reduced C-terminal telopeptide of type I collagen, indicating less bone resorption in vivo. These data suggest that the impaired macrophage differentiation and osteoclast bone resorptive activity play an important role in increased bone mass in Erk1−/− mice. Finally, to verify that the macrophage-osteoclast lineage is a key cell lineage for the phenotypic changes in vivo in Erk1−/− mice, we performed bone marrow transplantation. WT mice reconstituted long-term with Erk1−/− hematopoietic stem cells demonstrated increased bone mineral density as compared to WT and Erk2−/− stem cell recipients, implicating marrow autonomous, Erk1-dependent macrophage differentiation and osteoclast bioactivity in vivo. Collectively, our in vitro and in vivo data demonstrate isoform-specific Erk function in macrophage while providing rationale for the development of a specific inhibitor for Erk1 that might be used for the treatment of dysplastic and erosive bone diseases. Disclosures: No relevant conflicts of interest to declare.
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Zhao, Mingxia, Lihong Shen, Zijun Ouyang, Manru Li, Guoliang Deng, Chenxi Yang, Wei Zheng, et al. "Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis." Journal of Molecular Cell Biology 12, no. 4 (June 6, 2019): 277–90. http://dx.doi.org/10.1093/jmcb/mjz050.
Повний текст джерелаАнотація:
Abstract Impairment of glucose (Glu) uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions. The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis. Our results showed that conditional deletion of hnRNP A1 in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet (HFD). Conditional knockout mice fed a HFD showed exacerbated obesity, insulin resistance, and hepatic steatosis. In vitro interference of hnRNP A1 in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake, whereas hnRNP A1 overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin. The expression and stability of glycogen synthase (gys1) mRNA were also decreased in the absence of hnRNP A1. Mechanistically, hnRNP A1 interacted with gys1 and stabilized its mRNA, thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue. Taken together, our findings are the first to show that reduced expression of hnRNP A1 in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.
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Patel-Hett, Sunita, Hongbei Wang, Antonija J. Begonja, Jonathan N. Thon, Eva C. Alden, Nancy J. Wandersee, Xiuli An, Narla Mohandas, John H. Hartwig, and Joseph E. Italiano. "The spectrin-based membrane skeleton stabilizes mouse megakaryocyte membrane systems and is essential for proplatelet and platelet formation." Blood 118, no. 6 (August 11, 2011): 1641–52. http://dx.doi.org/10.1182/blood-2011-01-330688.
Повний текст джерелаАнотація:
Abstract Megakaryocytes generate platelets by remodeling their cytoplasm first into proplatelets and then into preplatelets, which undergo fission to generate platelets. Although the functions of microtubules and actin during platelet biogenesis have been defined, the role of the spectrin cytoskeleton is unknown. We investigated the function of the spectrin-based membrane skeleton in proplatelet and platelet production in murine megakaryocytes. Electron microscopy revealed that, like circulating platelets, proplatelets have a dense membrane skeleton, the main fibrous component of which is spectrin. Unlike other cells, megakaryocytes and their progeny express both erythroid and nonerythroid spectrins. Assembly of spectrin into tetramers is required for invaginated membrane system maturation and proplatelet extension, because expression of a spectrin tetramer–disrupting construct in megakaryocytes inhibits both processes. Incorporation of this spectrin-disrupting fragment into a novel permeabilized proplatelet system rapidly destabilizes proplatelets, causing blebbing and swelling. Spectrin tetramers also stabilize the “barbell shapes” of the penultimate stage in platelet production, because addition of the tetramer-disrupting construct converts these barbell shapes to spheres, demonstrating that membrane skeletal continuity maintains the elongated, pre-fission shape. The results of this study provide evidence for a role for spectrin in different steps of megakaryocyte development through its participation in the formation of invaginated membranes and in the maintenance of proplatelet structure.
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Jheon, Andrew, Jun Chen, William Teo, Bernhard Ganss, Jaro Sodek, and Sela Cheifetz. "Temporal and Spatial Expression of a Novel Zinc Finger Transcription Factor, AJ18, in Developing Murine Skeletal Tissues." Journal of Histochemistry & Cytochemistry 50, no. 7 (July 2002): 973–82. http://dx.doi.org/10.1177/002215540205000711.
Повний текст джерелаАнотація:
Bone morphogenetic proteins (BMPs) are characterized by their ability to induce osteoblastic differentiation. However, the mechanism of osteo-induction by BMPs has yet to be determined. Using differential display we previously identified AJ18, a zinc finger transcription factor, as an immediate-early response gene to BMP-7. AJ18 was shown to bind to the osteoblast-specific element2 (OSE2) and to modulate transactivation by Runx2, a master gene in osteoblastic differentiation. Here we describe the temporal and spatial expression of AJ18 in developing mouse tissues. AJ18 mRNA expression was observed in most tissues, except liver, and was generally highest early in embryonic development, decreasing markedly after parturition. Consistent with immunohistochemical analysis, AJ18 mRNA expression was highest in the brain, kidney, and bone of 17 dpc (days post coitum) embryos. In endochondral bones of embryonic and 4-week-old mice, immunostaining for AJ18 was strong in the nuclei of proliferating and pre-hypertrophic chondrocytes, and osteoblasts, whereas there was low or no staining in hypertrophic chondrocytes. In teeth of embryonic and 4-week-old mice, nuclear staining was observed in precursor and mature ameloblasts, odontoblasts, and cementoblasts, respectively. In addition, in 4-week-old mice staining of AJ18 was observed within alveolar bone cells and periodontal ligament cells. In general, the spatial expression of AJ18 in skeletal and non-skeletal tissues of mouse embryos showed striking similarity to the expression of BMP-7 mRNA. Therefore, the expression of AJ18 is consistent with its perceived role as a transcriptional factor that regulates developmental processes downstream of BMP-7.
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Mohallem, Rodrigo, та Uma K. Aryal. "Quantitative Proteomics and Phosphoproteomics Reveal TNF-α-Mediated Protein Functions in Hepatocytes". Molecules 26, № 18 (8 вересня 2021): 5472. http://dx.doi.org/10.3390/molecules26185472.
Повний текст джерелаАнотація:
Increased secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), is often associated with adipose tissue dysregulation, which often accompanies obesity. High levels of TNFα have been linked to the development of insulin resistance in several tissues and organs, including skeletal muscle and the liver. In this study, we examined the complex regulatory roles of TNFα in murine hepatocytes utilizing a combination of global proteomic and phosphoproteomic analyses. Our results show that TNFα promotes extensive changes not only of protein levels, but also the dynamics of their downstream phosphorylation signaling. We provide evidence that TNFα induces DNA replication and promotes G1/S transition through activation of the MAPK pathway. Our data also highlight several other novel proteins, many of which are regulated by phosphorylation and play a role in the progression and development of insulin resistance in hepatocytes.