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Статті в журналах з теми "Gremlin 1"

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Автор: Grafiati

Опубліковано: 10 грудня 2022

Оновлено: 28 січня 2023

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1

Claesson-Welsh, Lena. "Gremlin: vexing VEGF receptor agonist." Blood 116, no. 18 (November 4, 2010): 3386–87. http://dx.doi.org/10.1182/blood-2010-09-299412.

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Abstract Gremlins are mischievous creatures in English folklore, believed to be the cause of otherwise unexplainable breakdowns (the word gremlins is derived from the Old English “gremian” or “gremman,” “to vex”). Gremlin (or Gremlin-1) is also the designation of a secreted protein that is known to regulate bone formation during development. In this issue of Blood, Mitola et al report the novel role of Gremlin as a VEGFR2 agonist1 and the function of the Gremlin protein seems vexing indeed.

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2

Beck, Sandra, Thomas Simmet, Iris Müller, Florian Lang, and Meinrad Gawaz. "Gremlin-1 C-Terminus Regulates Function of Macrophage Migration Inhibitory Factor (MIF)." Cellular Physiology and Biochemistry 38, no. 2 (2016): 801–8. http://dx.doi.org/10.1159/000443035.

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Background/Aims: The counterbalance of macrophage migration inhibitory factor (MIF) and Gremlin-1 is a useful tool to predict the acuity of coronary artery disease (CAD) and plaque stability. Gremlin1 is an endogenous antagonist of MIF and therefore influences plaque vulnerability. This study was designed to elucidate the mechanistic basis determining the biophysical binding of Gremlin-1 to MIF. Methods: An in silico model suggested that several charged C-terminal amino acids are crucial in mediating Gremlin-1/MIF-binding. We produced several single amino acid exchange mutants of Gremlin-1 by site-directed mutagenesis. These Gremlin-1 mutants were tested for their ability to reduce MIF effects on monocytes. Results: We observed that the critical element of the Gremlin-1 molecule for regulating MIF-induced chemotactic activity lies at the C-terminal region. A single amino acid exchange of an arginine to an alanine residue is sufficient to abolish the antagonistic effect of Gremlin-1 on MIF. Therefore, the Gremlin-1 mutant R172A failed to reduce MIF-induced monocyte differentiation into macrophages. Conclusion: Gremlin-1 C-terminus is essential for antagonizing MIF effects. Our results could offer a novel strategy utilizing Gremlin-1 to target pro-inflammatory effects of MIF in various diseases.

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3

Chatterjee, Madhumita, Alexander Behrendt, Martina Schmid, Sandra Beck, Martina Schneider, Andreas Mack, Iris Müller, Tobias Geisler, and Meinrad Gawaz. "Platelets as a novel source of Gremlin-1: Implications for thromboinflammation." Thrombosis and Haemostasis 117, no. 02 (2017): 311–24. http://dx.doi.org/10.1160/th16-08-0665.

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SummaryPlatelets mediating haemostasis-thrombosis are central players in coronary artery disease (CAD). We characterised platelets as a novel source of Gremlin-1. Platelets express Gremlin-1 like inflammatory and endothelial cells. Gremlin-1 co-localised with P-selectin containing randomly distributed α–granules under resting state, which were peripheralised following platelet activation or adhesion over fibrinogen-coated surface. Gremlin-1 release upon activation with ADP, CRP, and TRAP was detected as enhanced surface expression; also in activated platelet supernatant as detected by Western Blot following CRP activation and by ELISA upon activation with ADP, CRP, PAR-1, and PAR4 agonist. Recombinant (rh)Gremlin-1 synergistically enhanced CRP-triggered intracellular calcium mobilisation, ADP-TRAP induced platelet activation, aggregation, and thrombin-activation triggered apoptosis; also thrombus formation ex vivo. Intracellular localisation of macrophage migration inhibitory factor (MIF) and Gremlin-1 a high-affinity binding partner and functional antagonist of MIF were found in intracoronary thrombus sections from acute coronary syndrome (ACS) patients and showed moderate overlap in α-granules of platelets. Intra-platelet Gremlin-1 levels were significantly decreased in ACS patients as compared to stable CAD (n=235). rhGremlin-1 also counteracted the anti-apoptotic and anti-thrombotic effects of rhMIF on platelets. Platelet-derived-Gremlin-1 prompted monocyte migration, facilitated adhesion under static and dynamic arterial flow conditions to collagen-adherent activated platelets; supported monocyte survival against BH-3-mimetic–induced apoptosis and macrophage differentiation in monocyte-platelet co-culture system, which were counteracted upon Gremlin-1 neutralisation. Thus platelet derived Gremlin-1 might contribute to the elevated circulating levels of Gremlin-1 in ACS and serve as a thrombo-inflammatory mediator in cardiovascular pathophysiologies.

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4

Rowan, Simon C., Lucie Piouceau, Joanna Cornwell, Lili Li, and Paul McLoughlin. "Gremlin 1 blocks vascular endothelial growth factor signaling in the pulmonary microvascular endothelium." Pulmonary Circulation 10, no. 1 (October 4, 2018): 204589401880720. http://dx.doi.org/10.1177/2045894018807205.

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The bone morphogenetic protein (BMP) antagonist gremlin 1 plays a central role in the pathogenesis of hypoxic pulmonary hypertension (HPH). Recently, non-canonical functions of gremlin 1 have been identified, including specific binding to the vascular endothelial growth factor receptor-2 (VEGFR2). We tested the hypothesis that gremlin 1 modulates VEGFR2 signaling in the pulmonary microvascular endothelium. We examined the effect of gremlin 1 haploinsufficiency on the expression of VEGF responsive genes and proteins in the hypoxic (10% O2) murine lung in vivo. Using human microvascular endothelial cells in vitro we examined the effect of gremlin 1 on VEGF signaling. Gremlin 1 haploinsufficiency (Grem1+/–) attenuated the hypoxia-induced increase in gremlin 1 observed in the wild-type mouse lung. Reduced gremlin 1 expression in hypoxic Grem1+/– mice restored VEGFR2 expression and endothelial nitric oxide synthase (eNOS) expression and activity to normoxic values. Recombinant monomeric gremlin 1 inhibited VEGFA-induced VEGFR2 activation, downstream signaling, and VEGF-induced increases in Bcl-2, cell number, and the anti-apoptotic effect of VEGFA in vitro. These results show that the monomeric form of gremlin 1 acts as an antagonist of VEGFR2 activation in the pulmonary microvascular endothelium. Given the previous demonstration that inhibition of VEGFR2 causes marked worsening of HPH, our results suggest that increased gremlin 1 in the hypoxic lung, in addition to blocking BMP receptor type-2 (BMPR2) signaling, contributes importantly to the development of PH by a non-canonical VEGFR2 blocking activity.

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5

Mitola, Stefania, Cosetta Ravelli, Michela Corsini, Alessandra Gianoncelli, Federico Galvagni, Kurt Ballmer-Hofer, Marco Presta, and Elisabetta Grillo. "Production and Biochemical Characterization of Dimeric Recombinant Gremlin-1." International Journal of Molecular Sciences 23, no. 3 (January 21, 2022): 1151. http://dx.doi.org/10.3390/ijms23031151.

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Gremlin-1 is a secreted cystine-knot protein that acts as an antagonist of bone morphogenetic proteins (BMPs), and as a ligand of heparin and the vascular endothelial growth factor receptor 2 (VEGFR2), thus regulating several physiological and pathological processes, including embryonic development, tissue fibrosis and cancer. Gremlin-1 exerts all these biological activities only in its homodimeric form. Here, we propose a multi-step approach for the expression and purification of homodimeric, fully active, histidine-tagged recombinant gremlin-1, using mammalian HEK293T cells. Ion metal affinity chromatography (IMAC) of crude supernatant followed by heparin-affinity chromatography enables obtaining a highly pure recombinant dimeric gremlin-1 protein, exhibiting both BMP antagonist and potent VEGFR2 agonist activities.

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6

Elemam, Noha Mousaad, Abdullah Imadeddin Malek, Esraa Elaraby Mahmoud, Waseem El-Huneidi, and Iman M. Talaat. "Insights into the Role of Gremlin-1, a Bone Morphogenic Protein Antagonist, in Cancer Initiation and Progression." Biomedicines 10, no. 2 (January 28, 2022): 301. http://dx.doi.org/10.3390/biomedicines10020301.

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The bone morphogenic protein (BMP) antagonist Gremlin-1 is a biologically significant regulator known for its crucial role in tissue differentiation and embryonic development. Nevertheless, it has been reported that Gremlin-1 can exhibit its function through BMP dependent and independent pathways. Gremlin-1 has also been reported to be involved in organ fibrosis, which has been correlated to the development of other diseases, such as renal inflammation and diabetic nephropathy. Based on growing evidence, Gremlin-1 has recently been implicated in the initiation and progression of different types of cancers. Further, it contributes to the stemness state of cancer cells. Herein, we explore the recent findings on the role of Gremlin-1 in various cancer types, including breast, cervical, colorectal, and gastric cancers, as well as glioblastomas. Additionally, we highlighted the impact of Gremlin-1 on cellular processes and signaling pathways involved in carcinogenesis. Therefore, it was suggested that Gremlin-1 might be a promising prognostic biomarker and therapeutic target in cancers.

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7

Zhu, Zhenbiao, Xiaowei Xing, Shisi Huang, and Yuanyuan Tu. "NAT10 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells by Mediating N4-Acetylcytidine Modification of Gremlin 1." Stem Cells International 2021 (April 12, 2021): 1–10. http://dx.doi.org/10.1155/2021/8833527.

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Objective. To investigate the function of NAT10 in mesenchymal stem cell (MSC) osteogenic differentiation and study the mechanism by which NAT10 affects MSC osteogenesis by mediating Gremlin 1 N4-acetylcytidine (ac4C) modification. Methods. Osteogenic differentiation of MSCs was induced, and the osteogenic ability was evaluated with alizarin red S (ARS) and alkaline phosphatase (ALP) assays. The NAT10 expression level during MSC osteogenesis was measured by western blot (WB). MSCs were transfected with lentiviruses to inhibit (Sh-NAT10) or overexpress NAT10 (Over-NAT10), and the osteogenic differentiation ability was assessed by ARS, ALP, and osteogenic gene marker assays. β-Catenin, Akt, and Smad signaling pathway component activation levels were assessed, and the expression levels of key Smad signaling pathway molecules were determined by PCR and WB. The Gremlin 1 mRNA ac4C levels were analyzed using RIP-PCR, and the Gremlin 1 mRNA degradation rate was determined. Sh-Gremlin 1 was transfected to further investigate the role of NAT10 and Gremlin 1 in MSC osteogenesis. Results. During MSC osteogenesis, NAT10 expression, ARS staining, and the ALP level gradually increased. Decreasing NAT10 expression inhibited, and increasing NAT10 expression promoted MSC osteogenic differentiation. NAT10 affected the BMP/Smad rather than the Akt and β-Catenin signaling pathway activation by regulating Gremlin 1 expression. The Gremlin 1 mRNA ac4C level was positively regulated by NAT10, which accelerated Gremlin 1 degradation. Sh-Gremlin 1 abolished the promotive effect of NAT10 on MSC osteogenic differentiation. Conclusion. NAT10 positively regulated MSC osteogenic differentiation through accelerating the Gremlin 1 mRNA degradation by increasing its ac4C level. These results may provide new mechanistic insight into MSC osteogenesis and bone metabolism in vivo.

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8

Aoshima, Yoichiro, Yasunori Enomoto, Shigeki Muto, Shiori Meguro, Hideya Kawasaki, Isao Kosugi, Tomoyuki Fujisawa, et al. "Gremlin-1 for the Differential Diagnosis of Idiopathic Pulmonary Fibrosis Versus Other Interstitial Lung Diseases: A Clinical and Pathophysiological Analysis." Lung 199, no. 3 (March 26, 2021): 289–98. http://dx.doi.org/10.1007/s00408-021-00440-y.

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Abstract Purpose The differential diagnosis of interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF) versus other non-IPF ILDs, is important for selecting the appropriate treatment. This retrospective study aimed to explore the utility of gremlin-1 for the differential diagnosis. Methods Serum gremlin-1 concentrations were measured using an ELISA in 50 patients with IPF, 42 patients with non-IPF ILD, and 30 healthy controls. The baseline clinical data, including pulmonary functions, prognosis, and three serum biomarkers (Krebs von den Lungen-6 [KL6], surfactant protein-D [SP-D], and lactate dehydrogenase [LDH]), were obtained through a medical record review for analyzing their associations with serum gremlin-1 concentrations. To evaluate the origin of gremlin-1, we performed immunostaining on lung sections. Results Serum gremlin-1 concentrations were significantly higher in patients with IPF (mean concentration, 14.4 ng/mL), followed by those with non-IPF ILD (8.8 ng/mL) and healthy controls (1.6 ng/mL). The area under the curve for IPF versus non-IPF ILDs was 0.759 (95% confidence interval, 0.661–0.857), which was superior to that of KL6/SP-D/LDH. The sensitivity and specificity for gremlin-1 (cutoff, 10.4 ng/mL) was 72 and 69%, respectively. By contrast, serum gremlin-1 concentrations were not associated with the pulmonary functions nor the prognosis in all patients with ILDs. In immunostaining, the gremlin-1 was broadly upregulated in IPF lungs, particularly at myofibroblasts, bronchiolar/alveolar epithelium, and CD163-positive M2-like macrophages. Conclusions Gremlin-1 may be a useful biomarker to improve the diagnostic accuracy for IPF compared to non-IPF ILDs, suggesting a role of this molecule in the pathogenesis of IPF.

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9

Park, Sin-Aye. "Role of Gremlin-1 in Cancer." Biomedical Science Letters 24, no. 4 (December 31, 2018): 285–91. http://dx.doi.org/10.15616/bsl.2018.24.4.285.

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10

Lavoz, Carolina, Jonay Poveda, Laura Marquez-Exposito, Sandra Rayego-Mateos, Raul R. Rodrigues-Diez, Alberto Ortiz, Jesús Egido, Sergio Mezzano, and Marta Ruiz-Ortega. "Gremlin activates the Notch pathway linked to renal inflammation." Clinical Science 132, no. 11 (June 5, 2018): 1097–115. http://dx.doi.org/10.1042/cs20171553.

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Preclinical studies suggest that Gremlin participates in renal damage and could be a potential therapeutic target for human chronic kidney diseases. Inflammation is a common characteristic of progressive renal disease, and therefore novel anti-inflammatory therapeutic targets should be investigated. The Notch signaling pathway is involved in kidney development and is activated in human chronic kidney disease, but whether Gremlin regulates the Notch pathway has not been investigated. In cultured tubular cells, Gremlin up-regulated gene expression of several Notch pathway components, increased the production of the canonical ligand Jagged-1, and caused the nuclear translocation of active Notch-1 (N1ICD). In vivo administration of Gremlin into murine kidneys elicited Jagged-1 production, increased N1ICD nuclear levels, and up-regulated the gene expression of the Notch effectors hes-1 and hey-1. All these data clearly demonstrate that Gremlin activates the Notch pathway in the kidney. Notch inhibition using the γ-secretase inhibitor DAPT impaired renal inflammatory cell infiltration and proinflammatory cytokines overexpression in Gremlin-injected mice and in experimental models of renal injury. Moreover, Notch inhibition blocked Gremlin-induced activation of the canonical and noncanonical nuclear factor-κB (NF-κB) pathway, identifying an important mechanism involved in the anti-inflammatory actions of Notch inhibition. In conclusion, Gremlin activates the Notch pathway in the kidney and this is linked to NF-κB-mediated inflammation, supporting the hypothesis that Notch inhibition could be a potential anti-inflammatory strategy for renal diseases.

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11

Wellbrock, Jasmin, Jan K. Hennigs, Björn Schulz, Gabi Vohwinkel, Hans Jörg Baumann, Carsten Bokemeyer, Hans Klose, Walter Fiedler, and Nicole Lüneburg. "Circulating Plasma Levels of Bone Morphogenic Protein Antagonist Gremlin-1 Are Increased in Patients with Pulmonary Arterial Hypertension." Blood 120, no. 21 (November 16, 2012): 5189. http://dx.doi.org/10.1182/blood.v120.21.5189.5189.

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Abstract Abstract 5189 Background: Pulmonary arterial hypertension (PAH) is a severe and life-threatening disease. It is characterized by excessive growth of pulmonary artery endothelial and smooth muscle cells leading to a profound pulmonary artery remodeling and consequently increased pulmonary artery pressure and vascular resistance. Most patients with the heritable form of PAH harbor a mutation in the bone morphogenic protein (BMP) receptor 2 (BMPR2) resulting in dysregulated BMP signaling. In addition, aberrant BMP signaling was also observed in the idiopathic form of PAH although the underlying molecular mechanisms have not been elucidated. Recently, it was shown that BMP antagonist Gremlin-1 was elevated in pulmonary vessels of mice during development of hypoxic pulmonary hypertension (Cahill et al, Circulation. 2012;125(7):920–30). Methods and Results: The aim of this prospective study was to investigate the plasma levels of Gremlin-1 in PAH patients (Dana point classification group I) and to correlate Gremlin-1 levels to clinical and hemodynamic parameters. Thirty subjects were included in the study (19 patients with PAH treated at the PH clinics of the University Medical Center Hamburg-Eppendorf, Germany and 11 healthy volunteers) after giving informed consent. The mean Gremlin-1 plasma level was 2. 6-fold increased with 333 ± 160 ng/ml, in patients with pulmonary arterial hypertension compared to those of healthy control subjects with a mean Gremlin-1 plasma level of 118 ± 115 ng/ml (p=0. 001 in t-test). Gremlin-1 plasma levels of PAH patients were correlated to demographic, clinical and hemodynamic parameters including age, sex, 6-minute walk distance, systemic and pulmonary blood pressure & vascular resistance, lung function testing, NT-proBNP (N terminal pro-brain natriuretic peptide) and NYHA/WHO functional classification. A positive correlation between Gremlin-1 plasma levels and NT-proBNP plasma levels was observed (Spearman Rho 0. 809 with p<0. 001). Furthermore, a negative correlation was observed between the Gremlin-1 levels and the 6-minute walk distance (Spearman Rho −0. 522 with p=0. 032). Conclusion: The plasma levels of BMP antagonist Gremlin-1 are significantly elevated in patients with pulmonary arterial hypertension and may serve as new serological marker. Gremlin-1 might mirror the state of BMP dysregulation and represent a potential follow up marker under a future targeted therapy. Furthermore, since Gremlin-1 was shown to induce proliferative effects on both endothelial as well as smooth muscle cells, it might also contribute directly to the aberrant vessel growth observed in PAH. Gremlin-1 plasma levels of patients with pulmonary hypertension (n=19) were analyzed in an enzyme-linked immunosorbent assay. Compared to healthy subjects (n=11), mean plasma levels of Gremlin-1 were 2. 6-fold increased in PH patients (t-test p=0. 001). Box plots show the median (center horizontal line), the 25th to the 75th percentile (box) and the range (whiskers).** indicates p<0. 01. Disclosures: Hennigs: Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Actelion: Research Funding; GlaxoSmithKline: Honoraria; Novartis: Honoraria. Fiedler:Pfizer Inc. : Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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12

Kišonaitė, Miglė, Xuelu Wang, and Marko Hyvönen. "Structure of Gremlin-1 and analysis of its interaction with BMP-2." Biochemical Journal 473, no. 11 (May 27, 2016): 1593–604. http://dx.doi.org/10.1042/bcj20160254.

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We have determined the crystal structure of Gremlin-1 and analysed its interaction with BMP-2. Our results suggest that Gremlin-1 does not inhibit BMP-2 by direct 1:1 binding, but possibly has a novel mechanism of sequestering BMP-2 into a larger oligomeric complex.

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13

Koroglu, Nadiye, Begum Aydogan Mathyk, Esra Nur Tola, Berna Aslan Cetin, Ilkbal Temel Yuksel, Ismail Dag, and Gonca Yetkin Yıldırım. "Gremlin-1 and gremlin-2 levels in polycystic ovary syndrome and their clinical correlations." Gynecological Endocrinology 35, no. 7 (February 4, 2019): 604–7. http://dx.doi.org/10.1080/09513590.2019.1566452.

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14

Nilsson, Eric E., Ginger Larsen, and Michael K. Skinner. "Roles of Gremlin 1 and Gremlin 2 in regulating ovarian primordial to primary follicle transition." REPRODUCTION 147, no. 6 (June 2014): 865–74. http://dx.doi.org/10.1530/rep-14-0005.

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A network of extracellular signaling factors has previously been shown to act in concert to control the ovarian primordial to primary follicle transition. The current study was designed to investigate the roles of the endogenous bone morphogenetic protein (BMP) inhibitors Gremlin 1 (GREM1) and GREM2 in primordial follicle transition in the rat ovary. GREM1 and GREM2 treatments were found to reverse the effects of anti-Müllerian hormone (AMH) to inhibit follicle transition in a whole-ovary culture system. GREM1 reversed the effect of BMP4 to stimulate primordial follicle transition. Immunohistochemical studies showed that GREM2, but not GREM1, was present in primordial follicles suggesting that GREM2 may regulate primordial follicle transition in vivo. Co-immunoprecipitation studies indicated that GREM2 directly binds to AMH, as well as to BMP4. Transcriptome analyses of ovaries treated with GREM2 or GREM1 yielded negligible numbers of differentially expressed genes, suggesting that the immediate effects of GREM2 or GREM1 appear to be at the level of protein–protein interactions, rather than direct actions on the cells. A number of other ovarian growth factors were found to influence the expression of Grem2. Observations suggest that Grem2 is a part of the signaling network of growth factors that regulate the primordial to primary follicle transition. Insights into the regulatory networks affecting the pool of primordial follicles are important to understand the molecular basis for reproductive diseases such as primary ovarian insufficiency.

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15

Tejedor-Santamaria, Lucia, Jose Luis Morgado-Pascual, Laura Marquez-Exposito, Beatriz Suarez-Alvarez, Raul R. Rodrigues-Diez, Antonio Tejera-Muñoz, Vanessa Marchant, et al. "Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis." Pharmaceuticals 15, no. 2 (January 20, 2022): 121. http://dx.doi.org/10.3390/ph15020121.

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Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory disorders and experimental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs could regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model resembling human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, restoring podocyte numbers. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by modulation of NOTCH pathway. JQ1 inhibited the gene expression of the NOTCH effectors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis.

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16

Baboota, Ritesh K., Aidin Rawshani, Laurianne Bonnet, Xiangyu Li, Hong Yang, Adil Mardinoglu, Tamar Tchkonia, et al. "BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH." Nature Metabolism 4, no. 8 (August 22, 2022): 1007–21. http://dx.doi.org/10.1038/s42255-022-00620-x.

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AbstractThe role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.

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17

Marchant, Vanessa, Alejandra Droguett, Graciela Valderrama, M. Eugenia Burgos, Daniel Carpio, Bredford Kerr, Marta Ruiz-Ortega, Jesús Egido, and Sergio Mezzano. "Tubular overexpression of Gremlin in transgenic mice aggravates renal damage in diabetic nephropathy." American Journal of Physiology-Renal Physiology 309, no. 6 (September 15, 2015): F559—F568. http://dx.doi.org/10.1152/ajprenal.00023.2015.

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Diabetic nephropathy (DN) is currently a leading cause of end-stage renal failure worldwide. Gremlin was identified as a gene differentially expressed in mesangial cells exposed to high glucose and in experimental diabetic kidneys. We have described that Gremlin is highly expressed in biopsies from patients with diabetic nephropathy, predominantly in areas of tubulointerstitial fibrosis. In streptozotocin (STZ)-induced experimental diabetes, Gremlin deletion using Grem1 heterozygous knockout mice or by gene silencing, ameliorates renal damage. To study the in vivo role of Gremlin in renal damage, we developed a diabetic model induced by STZ in transgenic (TG) mice expressing human Gremlin in proximal tubular epithelial cells. The albuminuria/creatinuria ratio, determined at week 20 after treatment, was significantly increased in diabetic mice but with no significant differences between transgenic (TG/STZ) and wild-type mice (WT/STZ). To assess the level of renal damage, kidney tissue was analyzed by light microscopy (periodic acid-Schiff and Masson staining), electron microscopy, and quantitative PCR. TG/STZ mice had significantly greater thickening of the glomerular basement membrane, increased mesangial matrix, and podocytopenia vs. WT/STZ. At the tubulointerstitial level, TG/STZ showed increased cell infiltration and mild interstitial fibrosis. In addition, we observed a decreased expression of podocin and overexpression of monocyte chemoattractant protein-1 and fibrotic-related markers, including transforming growth factor-β1, Col1a1, and α-smooth muscle actin. Together, these results show that TG mice overexpressing Gremlin in renal tubules develop greater glomerular and tubulointerstitial injury in response to diabetic-mediated damage and support the involvement of Gremlin in diabetic nephropathy.

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18

Shi, Wei, Jingsong Zhao, Kathryn D. Anderson, and David Warburton. "Gremlin negatively modulates BMP-4 induction of embryonic mouse lung branching morphogenesis." American Journal of Physiology-Lung Cellular and Molecular Physiology 280, no. 5 (May 1, 2001): L1030—L1039. http://dx.doi.org/10.1152/ajplung.2001.280.5.l1030.

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Анотація:

Bone morphogenetic protein-4 (BMP-4) is a key morphogen for embryonic lung development that is expressed at high levels in the peripheral epithelium, but the mechanisms that modulate BMP-4 function in early mouse lung branching morphogenesis are unclear. Here, we studied the BMP-4 antagonist Gremlin, which is a member of the DAN family of BMP antagonists that can bind and block BMP-2/4 activity. The expression level of gremlin in embryonic mouse lungs is highest in the early embryonic pseudoglandular stage [embryonic days (E) 11.5–14.5] and is reduced during fetal lung maturation (E18.5 to postnatal day 1). In situ hybridization indicates that gremlin is diffusely expressed in peripheral lung mesenchyme and epithelium, but relatively high epithelial expression occurs in branching buds at E11.5 and in large airways after E16.5. In E11.5 lung organ culture, we found that exogenous BMP-4 dramatically enhanced peripheral lung epithelial branching morphogenesis, whereas reduction of endogenous gremlin expression with antisense oligonucleotides achieved the same gain-of-function phenotype as exogenous BMP-4, including increased epithelial cell proliferation and surfactant protein C expression. On the other hand, adenoviral overexpression of gremlin blocked the stimulatory effects of exogenous BMP-4. Therefore, our data support the hypothesis that Gremlin is a physiologically negative regulator of BMP-4 in lung branching morphogenesis.

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Wellbrock, Jasmin, Sara Sheikhzadeh, Veronika Bonk, Leticia Oliveira-Ferrer, Kristin Klaetschke, Thomas Streichert, Carsten Bokemeyer, Yskert von Kodolitsch та Walter Fiedler. "Gremlin-1 Is Overexpressed in Endothelial Cells of Patients with Loeys-Dietz Syndrome Due to Dysregulation of TGF-β Signalling",. Blood 118, № 21 (18 листопада 2011): 3269. http://dx.doi.org/10.1182/blood.v118.21.3269.3269.

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Abstract Abstract 3269 The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder with symptoms similar to those of Marfan syndrome and the vascular type of Ehlers-Danlos syndrome. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. Patients with LDS harbour a mutation in the transforming growth factor β (TGF-β) receptors TGFBR1 (also named ALK-5) or TGFBR2. Since the TGF-β pathway plays a crucial role in many cellular processes including angiogenesis, we focussed our analyses on endothelial cell dysfunction in patients with Loeys-Dietz syndrome. We isolated circulating outgrowth endothelial cells (OEC) from the peripheral blood of two LDS patients (one female, 54 years; one male, 26 years old) both harbouring a mutation in the TGFBR2 gene. Gene expression profiles of OEC clones were performed using Affymetrix Human Genome U133 Plus 2.0 Arrays and confirmed by quantitative PCR analysis for genes of interest. OEC clones isolated from age- and sex-matched healthy controls served as reference subjects. We demonstrate that several genes belonging to the TGF-β pathway had altered expression in OECs isolated from LDS patients compared to those from healthy controls. For example, mRNA levels of bone morphogenic proteins (BMP) 2 and 4 were decreased in both LDS OEC clones (mean decrease 4 and 6 fold, respectively) whereas gene expression of inhibitory downstream molecule SMAD-6 was increased 2-fold. In both analysed OEC clones from LDS patients, gene expression of BMP antagonist Gremlin-1 (also known as Drm) showed the most prominent dysregulation with a 1136-fold and 164-fold higher expression in LDS OECs compared to healthy controls, respectively. Interestingly, in OECs isolated from healthy donors, Gremlin-1 expression was significantly down-regulated after incubation with SB431542 (5 μM), a small molecule inhibitor of the TGF-β receptor complex (mean decrease 4 fold; t-test: p = 0.002; n = 6). In contrast, the stimulation of OEC clones with TGF-β1 (1 ng/ml) resulted in significant up-regulation of Gremlin-1 mRNA levels (mean increase 7 fold; t-test: p = 0.014; n = 6). Apparently, the up-regulation of Gremlin-1 in LDS OECs seems to mirror an activated TGF-β signalling cascade in outgrowth endothelial cells. These findings are in line with other studies published on LDS where hyperactivity of the TGF-β downstream signalling was demonstrated by higher phosphorylation levels of SMAD-2 in the aortic media of LDS patients (Loeys et al., Nat Genet. 2005 Mar;37(3):275–81). Gremlin-1 might represent a second gene supporting the concept of increased TGF-β signalling in Loeys-Dietz syndrome. Gremlin-1 itself displays opposing effects on angiogenesis. First, it is known as a pro-angiogenic factor and was recently shown to stimulate angiogenesis via direct binding to the VEGF receptor 2 (Mitola et al., Blood. 2010 Nov 4;116(18):3677–80). On the other hand, as antagonist of bone morphogenic proteins, Gremlin-1 possesses anti-angiogenic properties by suppressing pro-angiogenic effects of BMP-2 and BMP-4. In summary, we believe that due to its drastic up-regulation in OECs of LDS patients, Gremlin-1 represents a crucial effector of dysregulated TGF-β signalling in endothelial cells inducing vascular pathology in Loeys-Dietz syndrome. Disclosures: Fiedler: Pfizer: Research Funding.

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Sarker, Debashis, Udai Banerji, Sarah Patricia Blagden, Natalie Cook, T. R. Jeffry Evans, Elizabeth Ruth Plummer, Marina Braun, et al. "A multi-modular phase I/II study of UCB6114, a first-in-class, fully human IgG4P anti-Gremlin-1 monoclonal antibody, as monotherapy and in combination with mFOLFOX6 or trifluridine/tipiracil, for patients with advanced gastrointestinal (GI) tumors." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): TPS221. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.tps221.

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TPS221 Background: Despite recent advances, effective treatment for GI cancers remains a significant unmet medical need. Gremlin-1 is secreted by the peri-tumoral stroma and down-regulates bone morphogenetic proteins (BMP) -2, -4, and -7 (members of the transforming growth factor-β superfamily), thereby allowing malignant cell expansion, renewal, and a more treatment-resistant mesenchymal phenotype. Gremlin-1 mRNA is highly expressed in multiple solid tumors including >60% of colorectal, pancreatic and esophageal cancers. UCB6114 is a first-in-class, fully human IgG4P monoclonal antibody optimized for neutralizing the activity of human Gremlin-1 thereby restoring BMP signaling. Preclinical studies have demonstrated that UCB6114 binds to Gremlin-1, inhibits its pharmacological activity, and has antitumor activity in several in vivo mouse models (including several GI cancers). Methods: ONC001 (clinicaltrials.gov: NCT04393298) is an ongoing multi-part, multicenter, nonrandomized, open-label, Phase I/II study evaluating the safety, pharmacokinetics (PK) and antitumor activity of UCB6114 administered intravenously as monotherapy or in combination with selected standard of care (SOC) regimens. Eligible patients (pts) are: aged ≥18 years; resistant or refractory to standard therapy; ECOG performance status 0/1; and have adequate renal, hepatic and bone marrow function. In the Phase I monotherapy dose escalation and adaption part (part A and A1; modified rolling 6 design), up to 66 pts with advanced solid tumors associated with high levels of Gremlin-1 mRNA expression will be recruited. In parts B and C (modified toxicity probability interval design), up to 54 pts with locally advanced or metastatic colorectal, gastric or gastroesophageal junction adenocarcinomas will receive UCB6114 in escalating doses in combination with either mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) or trifluridine/tipiracil, given at SOC dosing and schedules. The overarching objective of the phase I parts of the study (Parts A‒C) is to identify the recommended phase II dose of UCB6114 either as monotherapy or in combination. The primary objective is to characterize the safety profile of UCB6114; secondary and exploratory objectives include PK, antitumor activity (RECIST v1.1), and pharmacodynamics (including circulating Gremlin-1). Enrollment in ONC001 began in July 2020; as of Sept 2021, four dose escalation levels in the monotherapy dose-escalation module (Part A) have been completed without DLT. Recruitment to parts B and C is due to commence in Q4 2021. Clinical trial information: NCT04393298.

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21

Li, Qian, Yongwei Huo, Yonghong Guo, Xiaoyan Zheng, Wengang Sun, and Zhiming Hao. "Generation and Applications of a DNA Aptamer against Gremlin-1." Molecules 22, no. 5 (April 28, 2017): 706. http://dx.doi.org/10.3390/molecules22050706.

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22

Al-Najeem, Hadeel Thaeir, and Arshad Noori Ghani Al-Dujaili. "Assessment of Gremlin-1 Level in Pulmonary arterial hypertension disease." Research Journal of Pharmacy and Technology 10, no. 11 (2017): 3803. http://dx.doi.org/10.5958/0974-360x.2017.00690.4.

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23

Karagiannis, George S., Natasha Musrap, Punit Saraon, Ann Treacy, David F. Schaeffer, Richard Kirsch, Robert H. Riddell, and Eleftherios P. Diamandis. "Bone morphogenetic protein antagonist gremlin-1 regulates colon cancer progression." Biological Chemistry 396, no. 2 (February 1, 2015): 163–83. http://dx.doi.org/10.1515/hsz-2014-0221.

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Abstract Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.

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Koli, Katri, Frank Wempe, Anja Sterner-Kock, Anna Kantola, Martina Komor, Wolf-K. Hofmann, Harald von Melchner та Jorma Keski-Oja. "Disruption of LTBP-4 function reduces TGF-β activation and enhances BMP-4 signaling in the lung". Journal of Cell Biology 167, № 1 (4 жовтня 2004): 123–33. http://dx.doi.org/10.1083/jcb.200403067.

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Disruption of latent TGF-β binding protein (LTBP)–4 expression in the mouse leads to abnormal lung development and colorectal cancer. Lung fibroblasts from these mice produced decreased amounts of active TGF-β, whereas secretion of latent TGF-β was significantly increased. Expression and secretion of TGF-β2 and -β3 increased considerably. These results suggested that TGF-β activation but not secretion would be severely impaired in LTBP-4 −/− fibroblasts. Microarrays revealed increased expression of bone morphogenic protein (BMP)–4 and decreased expression of its inhibitor gremlin. This finding was accompanied by enhanced expression of BMP-4 target genes, inhibitors of differentiation 1 and 2, and increased deposition of fibronectin-rich extracellular matrix. Accordingly, increased expression of BMP-4 and decreased expression of gremlin were observed in mouse lung. Transfection of LTBP-4 rescued the −/− fibroblast phenotype, while LTBP-1 was inefficient. Treatment with active TGF-β1 rescued BMP-4 and gremlin expression to wild-type levels. Our results indicate that the lack of LTBP-4–mediated targeting and activation of TGF-β1 leads to enhanced BMP-4 signaling in mouse lung.

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25

Kudryashova, Tatiana, Yuanjun Shen, Andressa Pena, Emily Cronin, Evelyn Okorie, Dmitry Goncharov та Elena Goncharova. "Inhibitory Antibodies against Activin A and TGF-β Reduce Self-Supported, but Not Soluble Factors-Induced Growth of Human Pulmonary Arterial Vascular Smooth Muscle Cells in Pulmonary Arterial Hypertension". International Journal of Molecular Sciences 19, № 10 (28 вересня 2018): 2957. http://dx.doi.org/10.3390/ijms19102957.

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Increased growth and proliferation of distal pulmonary artery vascular smooth muscle cells (PAVSMC) is an important pathological component of pulmonary arterial hypertension (PAH). Transforming Growth Factor-β (TGF-β) superfamily plays a critical role in PAH, but relative impacts of self-secreted Activin A, Gremlin1, and TGF-β on PAH PAVSMC growth and proliferation are not studied. Here we report that hyper-proliferative human PAH PAVSMC have elevated secretion of TGF-β1 and, to a lesser extent, Activin A, but not Gremlin 1, and significantly reduced Ser465/467-Smad2 and Ser423/425-Smad3 phosphorylation compared to controls. Media, conditioned by PAH PAVSMC, markedly increased Ser465/467-Smad2, Ser423/425-Smad3, and Ser463/465-Smad1/5 phosphorylation, up-regulated Akt, ERK1/2, and p38 MAPK, and induced significant proliferation of non-diseased PAVSMC. Inhibitory anti-Activin A antibody reduced PAH PAVSMC growth without affecting canonical (Smads) or non-canonical (Akt, ERK1/2, p38 MAPK) effectors. Inhibitory anti-TGF-β antibody significantly reduced P-Smad3, P-ERK1/2 and proliferation of PAH PAVSMC, while anti-Gremlin 1 had no anti-proliferative effect. PDGF-BB diminished inhibitory effects of anti-Activin A and anti-TGF-β antibodies. None of the antibodies affected growth and proliferation of non-diseased PAVSMC induced by PAH PAVSMC-secreted factors. Together, these data demonstrate that human PAH PAVSMC have secretory, proliferative phenotype that could be targeted by anti-Activin A and anti-TGF-β antibodies; potential cross-talk with PDGF-BB should be considered while developing therapeutic interventions.

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Kara, Sevgul, and Metin Karakok. "Investigation of GREMLIN 1, COL15A1 immunoreactivity and the relationship between microvessel density and GREMLIN 1 in papillary renal cell carcinoma and chromophobe renal cell carcinoma." Medical Science and Discovery 3, no. 4 (April 15, 2016): 184. http://dx.doi.org/10.17546/msd.61375.

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Costello, Christine M., Katherine Howell, Edwina Cahill, Jean McBryan, Melanie Konigshoff, Oliver Eickelberg, Sean Gaine, Finian Martin, and Paul McLoughlin. "Lung-selective gene responses to alveolar hypoxia: potential role for the bone morphogenetic antagonist gremlin in pulmonary hypertension." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 2 (August 2008): L272—L284. http://dx.doi.org/10.1152/ajplung.00358.2007.

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Pulmonary hypoxia is a common complication of chronic lung diseases leading to the development of pulmonary hypertension. The underlying sustained increase in vascular resistance in hypoxia is a response unique to the lung. Thus we hypothesized that there are genes for which expression is altered selectively in the lung in response to alveolar hypoxia. Using a novel subtractive array strategy, we compared gene responses to hypoxia in primary human pulmonary microvascular endothelial cells (HMVEC-L) with those in cardiac microvascular endothelium and identified 90 genes (forming 9 clusters) differentially regulated in the lung endothelium. From one cluster, we confirmed that the bone morphogenetic protein (BMP) antagonist, gremlin 1, was upregulated in the hypoxic murine lung in vivo but was unchanged in five systemic organs. We also demonstrated that gremlin protein was significantly increased by hypoxia in vivo and inhibited HMVEC-L responses to BMP stimulation in vitro. Furthermore, significant upregulation of gremlin was measured in lungs of patients with pulmonary hypertensive disease. From a second cluster, we showed that CXC receptor 7, a receptor for the proangiogenic chemokine CXCL12, was selectively upregulated in the hypoxic lung in vivo, confirming that our subtractive strategy had successfully identified a second lung-selective hypoxia-responsive gene. We conclude that hypoxia, typical of that encountered in pulmonary disease, causes lung-specific alterations in gene expression. This gives new insights into the mechanisms of pulmonary hypertension and vascular loss in chronic lung disease and identifies gremlin 1 as a potentially important mediator of vascular changes in hypoxic pulmonary hypertension.

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Kapoor, Varun N., Sören Müller, Shilpa Keerthivasan, Markus Brown, Cecile Chalouni, Elaine E. Storm, Alessandra Castiglioni, et al. "Gremlin 1+ fibroblastic niche maintains dendritic cell homeostasis in lymphoid tissues." Nature Immunology 22, no. 5 (April 26, 2021): 571–85. http://dx.doi.org/10.1038/s41590-021-00920-6.

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29

Kim, Minsoo, Soomin Yoon, Sukmook Lee, Seon Ah Ha, Hyun Kee Kim, Jin Woo Kim, and Junho Chung. "Gremlin-1 Induces BMP-Independent Tumor Cell Proliferation, Migration, and Invasion." PLoS ONE 7, no. 4 (April 13, 2012): e35100. http://dx.doi.org/10.1371/journal.pone.0035100.

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30

Yi, Jun, Qunhua Jin, Bin Zhang, Xinqiu Wu, and Dawei Ge. "Gremlin-1 Concentrations Are Correlated with the Severity of Knee Osteoarthritis." Medical Science Monitor 22 (October 29, 2016): 4062–65. http://dx.doi.org/10.12659/msm.897849.

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31

Stafford, D. A., L. J. Brunet, M. K. Khokha, A. N. Economides, and R. M. Harland. "Cooperative activity of noggin and gremlin 1 in axial skeleton development." Development 138, no. 5 (February 8, 2011): 1005–14. http://dx.doi.org/10.1242/dev.051938.

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Lee, E., J. Kim, Y. Bae, S. Park, J. Park, L. Che, and S. Oh. "526 The involvement of gremlin 1 in particulate matter-induced melanogenesis." Journal of Investigative Dermatology 142, no. 12 (December 2022): S271. http://dx.doi.org/10.1016/j.jid.2022.09.541.

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33

O'Reilly, S. "FRI0243 Is The BMP Antagonist Gremlin-1 A Target in Systemic Sclerosis?" Annals of the Rheumatic Diseases 75, Suppl 2 (June 2016): 521.3–521. http://dx.doi.org/10.1136/annrheumdis-2016-eular.3210.

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34

Zabkiewicz, C., L. Ye, R. Hargest, and W. Jiang. "Gremlin 1 expression correlates with prognostic features and survival in breast carcinoma." European Journal of Cancer 72 (February 2017): S17—S18. http://dx.doi.org/10.1016/s0959-8049(17)30136-3.

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35

Müller, Iris I., Madhumita Chatterjee, Martina Schneider, Oliver Borst, Peter Seizer, Tanja Schönberger, Sebastian Vogel, et al. "Gremlin-1 inhibits macrophage migration inhibitory factor-dependent monocyte function and survival." International Journal of Cardiology 176, no. 3 (October 2014): 923–29. http://dx.doi.org/10.1016/j.ijcard.2014.08.051.

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36

Graham, Julie R., Cara M. M. Williams, and Zhiyong Yang. "MicroRNA-27b Targets Gremlin 1 to Modulate Fibrotic Responses in Pulmonary Cells." Journal of Cellular Biochemistry 115, no. 9 (July 15, 2014): 1539–48. http://dx.doi.org/10.1002/jcb.24809.

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37

Silvério de Barros, Renata, Grazielle Suhett Dias, Ana Paula do Rosario, Fernanda Vieira Paladino, Gabriel Herculano Lopes, and Alexandre Holthausen Campos. "Gremlin-1 potentiates the dedifferentiation of VSMC in early stages of atherosclerosis." Differentiation 109 (September 2019): 28–33. http://dx.doi.org/10.1016/j.diff.2019.08.001.

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38

Rowan, Simon C., Hanne Jahns, Liberty Mthunzi, Lucie Piouceau, Joanna Cornwell, Róisín Doody, Stephen Frohlich, John J. Callanan, and Paul McLoughlin. "Gremlin 1 depletion in vivo causes severe enteropathy and bone marrow failure." Journal of Pathology 251, no. 2 (May 28, 2020): 117–22. http://dx.doi.org/10.1002/path.5450.

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39

Glister, Claire, Leanne Satchell, and Phil G. Knight. "Granulosal and thecal expression of bone morphogenetic protein- and activin-binding protein mRNA transcripts during bovine follicle development and factors modulating their expression in vitro." REPRODUCTION 142, no. 4 (October 2011): 581–91. http://dx.doi.org/10.1530/rep-11-0150.

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Evidence supports local roles for transforming growth factor β superfamily members including activins and bone morphogenetic proteins (BMP) in follicle development. Access of these ligands to signalling receptors is likely modulated by extracellular binding proteins (BP). In this study, we comparedex vivoexpression of four BPs (chordin, gremlin, noggin and follistatin) in granulosal (GC) and theca interna (TC) compartments of developing bovine antral follicles (1–18 mm). Effects of FSH and IGF on BMP and BP expression by cultured GC, and effects of LH and BMPs on BP expression by cultured TC were also examined. Follicular expression of all four BP transcripts was higher in GC than TC compartments (P<0.001) a finding confirmed by immunohistochemistry. Follicle category affected (P<0.01) gremlin and follistatin mRNA abundance, with a significant cell-type×follicle category interaction for chordin, follistatin and noggin. Noggin transcript abundance was lower (P<0.05) in GC of large ‘E-active’ than ‘E-inactive’ follicles while follistatin mRNA level was higher (P<0.01). FSH enhanced CYP19, FSHR, INHBA and follistatin by GC without affecting BMP or BMP–BP expression. IGF increased CYP19 and follistatin, reduced BMP4, noggin and gremlin but did not affect chordin orFSHRmRNA levels. LH increased TC androgen secretion but had no effect on BMP or BP expression. BMPs uniformly suppressed TC androgen production whilst increasing chordin, noggin and gremlin mRNA levels up to 20-fold (P<0.01). These findings support the hypothesis that extracellular BP, mostly from GC, contribute to the regulation of intrafollicular BMP/activin signalling. Enhancement of thecal BP expression by BMP implies an autoregulatory feedback role to prevent excessive signalling.

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Leijten, J. C. H., J. Emons, C. Sticht, S. van Gool, E. Decker, A. Uitterlinden, G. Rappold, et al. "Gremlin 1, Frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis." Arthritis & Rheumatism 64, no. 10 (September 28, 2012): 3302–12. http://dx.doi.org/10.1002/art.34535.

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41

Hu, Kongzu, Heyan Sun, Binjie Gui, and Cong Sui. "Gremlin-1 suppression increases BMP-2-induced osteogenesis of human mesenchymal stem cells." Molecular Medicine Reports 15, no. 4 (February 28, 2017): 2186–94. http://dx.doi.org/10.3892/mmr.2017.6253.

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Yin, Miao, Mira Tissari, Jenni Tamminen, Irene Ylivinkka, Mikko Rönty, Pernilla von Nandelstadh, Kaisa Lehti, Marko Hyytiäinen, Marjukka Myllärniemi, and Katri Koli. "Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma." Oncotarget 8, no. 58 (October 6, 2017): 98280–97. http://dx.doi.org/10.18632/oncotarget.21550.

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43

Yin, Miao, Mira Tissari, Jenni Tamminen, Irene Ylivinkka, Mikko Ronty, Kaisa Lehti, Marko Hyytiainen, Marjukka Myllarniemi, and Katri Koli. "OA02.02 Gremlin-1 is a Key Regulator of the Invasive Phenotype in Mesothelioma." Journal of Thoracic Oncology 12, no. 1 (January 2017): S246—S247. http://dx.doi.org/10.1016/j.jtho.2016.11.233.

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44

Gooding, Sarah, and Simon J. Leedham. "Gremlin 1 — small protein, big impact: the multiorgan consequences of disrupted BMP antagonism †." Journal of Pathology 251, no. 4 (June 20, 2020): 349–52. http://dx.doi.org/10.1002/path.5479.

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45

Li, Ruohan, Huaixiang Zhou, Mingzhe Li, Qiuyan Mai, Zhang Fu, Youheng Jiang, Changxue Li, et al. "Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways." Cells 11, no. 14 (July 7, 2022): 2136. http://dx.doi.org/10.3390/cells11142136.

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Cancer cell survival, function and fate strongly depend on endoplasmic reticulum (ER) proteostasis. Although previous studies have implicated the ER stress signaling network in all stages of cancer development, its role in cancer metastasis remains to be elucidated. In this study, we investigated the role of Gremlin-1 (GREM1), a secreted protein, in the invasion and metastasis of colorectal cancer (CRC) cells in vitro and in vivo. Firstly, public datasets showed a positive correlation between high expression of GREM1 and a poor prognosis for CRC. Secondly, GREM1 enhanced motility and invasion of CRC cells by epithelial–mesenchymal transition (EMT). Thirdly, GREM1 upregulated expression of activating transcription factor 6 (ATF6) and downregulated that of ATF4, and modulation of the two key players of the unfolded protein response (UPR) was possibly through activation of PI3K/AKT/mTOR and antagonization of BMP2 signaling pathways, respectively. Taken together, our results demonstrate that GREM1 is an invasion-promoting factor via regulation of ATF6 and ATF4 expression in CRC cells, suggesting GREM1 may be a potential pharmacological target for colorectal cancer treatment.

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46

Sung, Nam Ji, Na Hui Kim, Young-Joon Surh, and Sin-Aye Park. "Gremlin-1 Promotes Metastasis of Breast Cancer Cells by Activating STAT3-MMP13 Signaling Pathway." International Journal of Molecular Sciences 21, no. 23 (December 3, 2020): 9227. http://dx.doi.org/10.3390/ijms21239227.

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Gremlin-1 (GREM1), one of the bone morphogenetic protein (BMP) antagonists, can directly bind to BMPs. GREM1 is involved in organogenesis, tissue differentiation, and organ fibrosis. Recently, numerous studies have reported the oncogenic role of GREM1 in cancer. However, the role of GREM1 in metastasis of breast cancer cells and its underlying mechanisms remain poorly understood. The role of GREM1 in breast cancer progression was assessed by measuring growth, migration, and invasion of breast cancer cells. An orthotopic breast cancer mouse model was used to investigate the role of GREM1 in lung metastasis of breast cancer cells. GREM1 knockdown suppressed the proliferation of breast cancer cells, while its overexpression increased their growth, migration, and invasion. Cells with Grem1-knockdown showed much lower tumor growth rates and lung metastasis than control cells. GREM1 enhanced the expression of matrix metalloproteinase 13 (MMP13). A positive correlation between GREM1 and MMP13 expression was observed in breast cancer patients. GREM1 activated signal transducer and activator of transcription 3 (STAT3) transcription factor involved in the expression of MMP13. Our study suggests that GREM1 can promote lung metastasis of breast cancer cells through the STAT3-MMP13 pathway. In addition, GREM1 might be a promising therapeutic target for breast cancer metastasis.

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47

Wellbrock, Jasmin, Lars Harbaum, Hauke Stamm, Jan K. Hennigs, Björn Schulz, Hans Klose, Carsten Bokemeyer, Walter Fiedler, and Nicole Lüneburg. "Intrinsic BMP Antagonist Gremlin-1 as a Novel Circulating Marker in Pulmonary Arterial Hypertension." Lung 193, no. 4 (April 30, 2015): 567–70. http://dx.doi.org/10.1007/s00408-015-9735-5.

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Worthley, Daniel L., Michael Churchill, Jocelyn T. Compton, Yagnesh Tailor, Meenakshi Rao, Yiling Si, Daniel Levin, et al. "Gremlin 1 Identifies a Skeletal Stem Cell with Bone, Cartilage, and Reticular Stromal Potential." Cell 160, no. 1-2 (January 2015): 269–84. http://dx.doi.org/10.1016/j.cell.2014.11.042.

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Khatib Shahidi, Roxana, Jenny M. Hoffmann, Shahram Hedjazifar, Laurianne Bonnet, Ritesh K. Baboota, Stephanie Heasman, Christopher Church, et al. "Adult mice are unresponsive to AAV8-Gremlin1 gene therapy targeting the liver." PLOS ONE 16, no. 2 (February 19, 2021): e0247300. http://dx.doi.org/10.1371/journal.pone.0247300.

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Анотація:

Objective Gremlin 1 (GREM1) is a secreted BMP2/4 inhibitor which regulates commitment and differentiation of human adipose precursor cells and prevents the browning effect of BMP4. GREM1 is an insulin antagonist and serum levels are high in type 2 diabetes (T2D). We here examined in vivo effects of AAV8 (Adeno-Associated Viral vectors of serotype eight) GREM 1 targeting the liver in mature mice to increase its systemic secretion and also, in a separate study, injected recombinant GREM 1 intraperitoneally. The objective was to characterize systemic effects of GREM 1 on insulin sensitivity, glucose tolerance, body weight, adipose cell browning and other local tissue effects. Methods Adult mice were injected with AAV8 vectors expressing GREM1 in the liver or receiving regular intra-peritoneal injections of recombinant GREM1 protein. The mice were fed with a low fat or high fat diet (HFD) and followed over time. Results Liver-targeted AAV8-GREM1 did not alter body weight, whole-body glucose and insulin tolerance, or adipose tissue gene expression. Although GREM1 protein accumulated in liver cells, GREM1 serum levels were not increased suggesting that it may not have been normally processed for secretion. Hepatic lipid accumulation, inflammation and fibrosis were also not changed. Repeated intraperitoneal rec-GREM1 injections for 5 weeks were also without effects on body weight and insulin sensitivity. UCP1 was slightly but significantly reduced in both white and brown adipose tissue but this was not of sufficient magnitude to alter body weight. We validated that recombinant GREM1 inhibited BMP4-induced pSMAD1/5/9 in murine cells in vitro, but saw no direct inhibitory effect on insulin signalling and pAkt (ser 473 and thr 308) activation. Conclusion GREM1 accumulates intracellularly when overexpressed in the liver cells of mature mice and is apparently not normally processed/secreted. However, also repeated intraperitoneal injections were without effects on body weight and insulin sensitivity and adipose tissue UCP1 levels were only marginally reduced. These results suggest that mature mice do not readily respond to GREMLIN 1 but treatment of murine cells with GREMLIN 1 protein in vitro validated its inhibitory effect on BMP4 signalling while insulin signalling was not altered.

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Worthley, Daniel L., Michael Quante, Samuel Asfaha, Christoph B. Westphalen, Yagnesh H. Tailor, Jean-Philippe Pradere, Juliane S. Troeger, Robert Schwabe, and Timothy C. Wang. "552 The BMP Antagonist Gremlin 1 Labels a Mesenchymal Progenitor Cell in the Gastrointestinal Tract." Gastroenterology 142, no. 5 (May 2012): S—111. http://dx.doi.org/10.1016/s0016-5085(12)60417-x.

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