Matrix Gla protein regulates adipogenesis and is serum marker of visceral adiposity.
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ABSTRACT:
SUBMITTER: Li C
PROVIDER: S-EPMC6999844 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Valvular and vascular calcification are common causes of cardiovascular morbidity and mortality. Developing effective treatments requires understanding the molecular underpinnings of these processes. Shear stress is thought to play a role in inhibiting calcification. Furthermore, NOTCH1 regulates vascular and valvular endothelium, and human mutations in NOTCH1 can cause calcific aortic valve disease. Here, we determined the genome-wide impact of altering shear stress and NOTCH signaling on human aortic valve endothelium. mRNA-sequencing of primary human aortic valve endothelial cells (HAVECs) with or without knockdown of NOTCH1, in the presence or absence of shear stress, revealed NOTCH1-dependency of the atherosclerosis-related gene connexin 40 (GJA5), and numerous repressors of endochondral ossification. Among these, matrix gla protein (MGP) is highly expressed in aortic valve and vasculature, and inhibits soft tissue calcification by sequestering bone morphogenetic proteins (BMPs). Altering NOTCH1 levels affected MGP mRNA and protein in HAVECs. Furthermore, shear stress activated NOTCH signaling and MGP in a NOTCH1-dependent manner. NOTCH1 positively regulated endothelial MGP in vivo through specific binding motifs upstream of MGP. Our studies suggest that shear stress activates NOTCH1 in primary human aortic valve endothelial cells leading to downregulation of osteoblast-like gene networks that play a role in tissue calcification.
| S-EPMC4468000 | biostudies-literature
Project description:Matrix Gla Protein (MGP) is an ECM molecule commonly associated with dysfunctions of large blood vessels such as arteriosclerosis and atherosclerosis. However, the exact role of MGP in the microvasculature is not clear. Utilizing a mouse MGP knockout model we found that MGP suppresses angiogenic sprouting from mouse aorta restricts microvascular density in cardiac and skeletal muscle, and is an endogenous inhibitor of tumor angiogenesis. Similarly, morpholino based knockdown of MGP in zebrafish embryos caused a progressive loss of luminal structures in intersegmental vessels, a phenotype reminiscent of Dll4/Notch inhibition. Accordingly, MGP suppressed Notch-dependent Hes-1 promoter activity and expression of Jagged1 mRNA relative to Dll4 mRNA. However, inhibition of BMP but not Notch or VEGF signaling reversed the excessive angiogenic sprouting phenotype of MGP knockout aortic rings suggesting that MGP may normally suppress angiogenic sprouting by blocking BMP signaling. Collectively, these results suggest that MGP is a multi-functional inhibitor of normal and abnormal angiogenesis that may function by coordinating with both Notch and BMP signaling pathways.
| S-EPMC3629274 | biostudies-literature
Project description:Matrix Gla protein (Mgp) and bone Gla protein (Bgp) are vitamin-K dependent proteins that bind calcium in their γ-carboxylated versions in mammals. They are recognized as positive (Bgp) or negative (Mgp and Bgp) regulators of biomineralization in a number of tissues, including skeletal tissues of bony vertebrates. The Mgp/Bgp gene family is poorly known in cartilaginous fishes, which precludes the understanding of the evolution of the biomineralization toolkit at the emergence of jawed vertebrates. Here we took advantage of recently released genomic and transcriptomic data in cartilaginous fishes and described the genomic loci and gene expression patterns of the Mgp/Bgp gene family. We identified three genes, Mgp1, Mgp2, and Bgp, in cartilaginous fishes instead of the single previously reported Mgp gene. We describe their genomic loci, resulting in a dynamic evolutionary scenario for this gene family including several events of local (tandem) duplications, but also of translocation events, along jawed vertebrate evolution. We describe the expression patterns of Mgp1, Mgp2, and Bgp in embryonic stages covering organogenesis in the small-spotted catshark Scyliorhinus canicula and present a comparative analysis with Mgp/Bgp family members previously described in bony vertebrates, highlighting ancestral features such as early embryonic, soft tissues, and neuronal expressions, but also derived features of cartilaginous fishes such as expression in fin supporting fibers. Our results support an ancestral function of Mgp in skeletal mineralization and a later derived function of Bgp in skeletal development that may be related to the divergence of bony vertebrates.
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Project description:Arteriovenous malformations (AVMs) in organs, such as the lungs, intestine, and brain, are characteristic of hereditary hemorrhagic telangiectasia (HHT), a disease caused by mutations in activin-like kinase receptor 1 (ALK1), which is an essential receptor in angiogenesis, or endoglin. Matrix Gla protein (MGP) is an antagonist of BMPs that is highly expressed in lungs and kidneys and is regulated by ALK1. The objective of this study was to determine the role of MGP in the vasculature of the lungs and kidneys. We found that Mgp gene deletion in mice caused striking AVMs in lungs and kidneys, where overall small organ size contrasted with greatly increased vascularization. Mechanistically, MGP deficiency increased BMP activity in lungs. In cultured lung epithelial cells, BMP-4 induced VEGF expression through induction of ALK1, ALK2, and ALK5. The VEGF secretion induced by BMP-4 in Mgp-/- epithelial cells stimulated proliferation of ECs. However, BMP-4 inhibited proliferation of lung epithelial cells, consistent with the increase in pulmonary vasculature at the expense of lung tissue in the Mgp-null mice. Similarly, BMP signaling and VEGF expression were increased in Mgp-/- mouse kidneys. We therefore conclude that Mgp gene deletion is what we believe to be a previously unidentified cause of AVMs. Because lack of MGP also causes arterial calcification, our findings demonstrate that the same gene defect has drastically different effects on distinct vascular beds.
| S-EPMC3148746 | biostudies-literature
Project description:Recent studies showed that GPR30, a seven-transmembrane G-protein-coupled receptor, is a novel estrogen receptor (ER) that mediates some biological events elicited by estrogen in several types of cancer cells. However, its physiological or pathological role in vivo is unclear. Here, we show that GPR30 knockout (GPRKO) female mice were protected from high-fat diet (HFD)-induced obesity, blood glucose intolerance, and insulin resistance. The decreased body weight gain in GPRKO female mice is due to the reduction in body fat mass. These effects occurred in the absence of significant changes in food intake, intestinal fat absorption, triglyceride metabolism, or energy expenditure. However, GPR30 had no significant metabolic effects in male mice fed the HFD and both sexes of mice fed a chow diet. Further, GPR30 expression levels in fat tissues of WT obese female mice were greatly increased, whereas ERα and β expression was not altered. Deletion of GPR30 reduced adipogenic differentiation of adipose tissue-derived stromal cells. Conversely, activation of GPR30 enhanced adipogenic differentiation of 3T3-L1 preadipocytes. These findings provide evidence for the first time that GPR30 promotes adipogenesis and therefore the development of obesity in female mice exposed to excess fat energy.
| S-EPMC5048424 | biostudies-literature
Project description:ObjectiveThe composition of the extracellular matrix (ECM) impacts adipocyte function and might determine adipose tissue (AT) function and distribution. Cartilage oligomeric matrix protein (COMP), a matricellular protein usually studied in bone and cartilage, is highly differentially expressed between subcutaneous abdominal and gluteal AT. This study aimed to explore COMP's role in human subcutaneous abdominal and gluteal AT and preadipocyte biology.MethodsCOMP mRNA levels were measured in whole AT and immortalised preadipocytes via quantitative (q)-PCR. Tissue and cellular COMP protein were measured via Western blot and immunohistochemistry; plasma COMP was measured by ELISA. The effect of COMP on adipogenesis in immortalised preadipocytes was evaluated by qPCR of adipogenic markers and cellular triacylglycerol (TAG) accumulation.ResultsqPCR analysis of paired subcutaneous abdominal and gluteal AT biopsies (n = 190) across a range of BMI (20.7-45.5 kg/m2) indicated ?3-fold higher COMP expression in gluteal AT (P = 1.7 × 10-31); protein levels mirrored this. Immunohistochemistry indicated COMP was abundant in gluteal AT ECM and co-localised with collagen-1. AT COMP mRNA levels and circulating COMP protein levels were positively associated with BMI/adiposity but unrelated to AT distribution. COMP expression changed dynamically during adipogenesis (time × depot, P = 0.01). Supplementation of adipogenic medium with exogenous COMP protein (500 ng/ml) increased PPARG2 expression ?1.5-fold (P = 0.0003) and TAG accumulation ?1.25-fold in abdominal and gluteal preadipocytes (P = 0.02).ConclusionsWe confirmed that COMP is an ECM protein which is differentially expressed between subcutaneous abdominal and gluteal AT. Despite its depot-specific expression pattern, however, AT COMP mRNA levels and plasma COMP concentration correlated positively with overall obesity but not body fat distribution. Exogenous COMP enhanced adipogenesis. These data identify COMP as a novel regulator of AT and highlight the importance of the ECM to AT biology.
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Project description: Not available
| S-EPMC4373345 | biostudies-literature
Project description:BackgroundCalcification of renal allografts is common in the first year after transplantation and is related to hyperparathyroidism. It is associated with an impaired long-term function of the graft (Am J Transplant 5?1934-41, 2005). Aim of this study is to examine the role of the anti-calcifying/calcifying factors in the pathophysiology of renal allograft calcification.MethodsWe analyzed protocol allograft biopsies, blood and urine samples of 31 patients with and 27 patients without allograft calcification taken at 6 weeks, 3 and 6 months after transplantation. Patient demographical data, cold ischemia time, initial graft function and donor characteristics were comparable between the two groups. Biopsies were stained for osteopontin, fetuin, and matrix-gla-protein. Serum and urine electrolytes, matrix-gla-protein, fetuin, Vitamin D and intact parathyroid hormone in serum and osteopontin (OPN) in urine were examined.ResultsSerum levels of fetuin and matrix-Gla protein as well as urinary levels of OPN showed specific time dependent changes (6 weeks vs. 3 months vs. 6 months; all p<0.0001). In patients with calcifications, urinary levels of OPN were decreased by 55% at 6 weeks and increased thereafter, showing 54% higher levels at 6 months compared to patients without calcification (6 weeks: p<0.01, 6 months: p<0.05). Local protein expression of fetuin-A, matrix-Gla protein and OPN in the graft was specifically increased around calcified plaques, without differences in the mRNA tissue expression.ConclusionAnticalcifying factors show significant changes in the early phase after renal transplantation, which may be important for the prevention of allograft calcification. The differences in OPN indicate an involvement of this factor in the regulation of calcification.
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Project description:Genetic and environmental factors may lead to abnormal growth of the orofacial skeleton, affecting the overall structure of the face. In this study, we investigated the craniofacial abnormalities in a mouse model for Keutel syndrome, a rare genetic disease caused by loss-of-function mutations in the matrix Gla protein (MGP) gene. Keutel syndrome patients show diffuse ectopic calcification of cartilaginous tissues and impaired midface development. Our comparative cephalometric analyses of micro-computed tomography images revealed a severe midface hypoplasia in Mgp-/- mice. In vivo reporter studies demonstrated that the Mgp promoter is highly active at the cranial sutures, cranial base synchondroses, and nasal septum. Interestingly, the cranial sutures of the mutant mice showed normal anatomical features. Although we observed a mild increase in mineralization of the spheno-occipital synchondrosis, it did not reduce the relative length of the cranial base in comparison with total skull length. Contrary to this, we found the nasal septum to be abnormally mineralized and shortened in Mgp-/- mice. Transgenic restoration of Mgp expression in chondrocytes fully corrected the craniofacial anomalies caused by MGP deficiency, suggesting a local role for MGP in the developing nasal septum. Although there was no up-regulation of markers for hypertrophic chondrocytes, a TUNEL assay showed a marked increase in apoptotic chondrocytes in the calcified nasal septum. Transmission electron microscopy confirmed unusual mineral deposits in the septal extracellular matrix of the mutant mice. Of note, the systemic reduction of the inorganic phosphate level was sufficient to prevent abnormal mineralization of the nasal septum in Mgp-/-;Hyp compound mutants. Our work provides evidence that modulation of local and systemic factors regulating extracellular matrix mineralization can be possible therapeutic strategies to prevent ectopic cartilage calcification and some forms of congenital craniofacial anomalies in humans.
| S-EPMC5500805 | biostudies-literature
Project description:The MGP single nucleotide polymorphism (SNP) rs1800801 has previously been associated with recurrent ischemic stroke in a Spanish cohort. Here, we tested for association of this SNP with ischemic stroke recurrence in a North American Caucasian cohort. Acute ischemic stroke patients admitted between 10/2009 and 12/2016 at three hospitals within a large healthcare system in the northeastern United States that were enrolled in a healthcare system-wide exome sequencing program were retrospectively reviewed. Patients with recurrent stroke within 1 year after index event were compared to those without recurrence. Of 9,348 suspected acute ischemic strokes admitted between 10/2009 and 12/2016, 1,727 (18.5%) enrolled in the exome-sequencing program. Among those, 1,068 patients had exome sequencing completed and were eligible for inclusion. Recurrent stroke within the first year of stroke was observed in 79 patients (7.4%). In multivariable analysis, stroke prior to the index stroke (OR 9.694, 95% CI 5.793-16.224, p ≤ 0.001), pro-coagulant status (OR = 3.563, 95% CI 1.504-8.443, p = 0.004) and the AA genotype of SNP rs1800801 (OR = 2.408, 95% CI 1.079-4.389, p = 0.004) were independently associated with recurrent stroke within the first year. The AA genotype of the MGP SNP rs1800801 is associated with recurrence within the first year after ischemic stroke in North American Caucasians. Study of stroke subtypes and additional populations will be required to determine if incorporation of allelic status at this SNP into current risk scores improves prediction of recurrent ischemic stroke.
| S-EPMC7316322 | biostudies-literature