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MGP

Official Full Name
matrix Gla protein
Background
The protein encoded by this gene is secreted and likely acts as an inhibitor of bone formation. The encoded protein is found in the organic matrix of bone and cartilage. Defects in this gene are a cause of Keutel syndrome (KS). Two transcript variants encoding different isoforms have been found for this gene.
Synonyms
matrix Gla protein; Cell growth-inhibiting gene 36 protein; MGLAP; NTI; OTTHUMP00000239335; MGP; GIG36; OTTHUMP00000239337

Matrix Gla protein (MGP) is a vitamin K-dependent protein that inhibits vascular and cartilage calcification in the human body and has an important influence on bone formation and cartilage degeneration. It has 5 carboxylated glutamic acid residues and multiple phosphorylated serine residues, which exist in different molecular forms in serum and synovial fluid, including phosphorylated MGP, non-phosphorylated MGP, carboxylation MGP, and non-carboxylated MGP (ucMGP).

Inactive MGP can modulate its activity by converting the inactive MGP protein residues to form a phosphorylated or carboxylated MGP protein by vitamin K2-dependent invertase: γ-carboxylase and phosphorylase. MGP regulates bone calcification and cartilage differentiation in chondrocytes and bone tissue. In the circulatory system, secretion of MGP by vascular endothelial cells inhibits vascular ectopic calcification. In the model of ethylene glycol-induced rat kidney uric acid calculus, it was found that renal tubular epithelial cells expressed a significant increase in MGP.

MGP.pngFigure 1. Matrix Gla protein (MGP) inhibits the osteoinductive function of bone morphogenetic protein (BMP). (Michael Böhm., et al. 2015)

Modulation of OA by MGP

Osteoarthritis (OA) is a chronic degenerative heterogeneous disease in the middle-aged and elderly people, and the knee joint is most often affected. MGP can be quantitatively detected in the non-activated form of ucMGP in the serum and knee synovial fluid of patients. Studies have shown that in patients with OA, the ucMGP in the synovial fluid of the inflammatory group was significantly higher than that in the non-inflammatory group, and was positively correlated with ESR, but the ucMGP in serum and synovial fluid of OA patients was significantly lower than that of the control group. Bing et al. reported that in 178 patients with OA, the ucMGP content in the synovial fluid of the knee was significantly negatively correlated with the severity of the patient's imaging (according to the Kellgren-Lawrence classification). Serum ucMGP was significantly lower than the control group and was not meaningful with imaging severity. This may be due to a small sample size or other disease that interferes with serum ucMGP concentrations.

The vitamin K-dependent carboxylase converts the γ-Gly residue of the unactivated MGP protein into a γ-Gla residue to activate it, thereby exerting its effect of inhibiting heterotopic ossification. The γ-Gla residue and the phosphorylated group can bind to local calcium ions on the surface of the vascular endothelium, reduce local calcium ion concentration, and inhibit local calcium deposition. MGP can be combined with bone morphogenetic protein-2 (BMP-2) to reduce local BMP-2 concentration and inhibit osteocalcification. MGP binds to specific sites III1-C of fibrin, thereby enhancing cell adhesion and inhibiting local lesion formation.

MGP and OA Related Signal Pathway

The Notch signaling pathway has been shown to be a classic signaling pathway for knee arthritis, which is rarely expressed in healthy adult knee cartilage, but is abundantly expressed in degenerated or calcified chondrocytes and is involved in the self-repair of chondrocytes. Studies have shown that MGP deficiency enhances the activation of the receptor proteins Jagged1 and Jagged2 in the Notch signaling pathway and regulates the expression of the Notch signaling pathway. In addition, White et al. found that Notch1 directly regulates MGP expression and binds to the CSL binding site in the signaling pathway through specific enhancers to regulate MGP gene transcription.

Runx2 is one of the important transcription factors of the Wnt/B-catenin signaling pathway, which regulates the differentiation of mesenchymal cells into osteoblasts. Runx2 also activates the MGP gene, regulates MGP expression, and exogenously overexpresses Runx2 and upregulates MGP transcription. Studies have shown that parathyroid hormone regulates transcription of MGP genes in osteoblasts by regulating Runx2.

References:

  1. Bing, W. , & Feng, L. . (2015). Attenuate synovial fluid uncarboxylated matrix gla-protein (ucmgp) concentrations are linked with radiographic progression in knee psteoarthritis.
  2. White, M. P. , Theodoris, C. V. , Liu, L. , Collins, W. J. , Blue, K. W. , & Lee, J. H. , et al. (2015). Notch1 regulates matrix gla protein and calcification gene networks in human valve endothelium. Journal of Molecular and Cellular Cardiology, 84, 13-23.
  3. Michael Böhm, Ezekowitz, M. D. , Connolly, S. J. , Eikelboom, J. W. , & Wallentin, L. . (2015). Changes in renal function in patients with atrial fibrillation: an analysis from the rely trial. Journal of the American College of Cardiology, 65(23).

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