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Gene Review

MGP  -  matrix Gla protein

Homo sapiens

Synonyms: Cell growth-inhibiting gene 36 protein, GIG36, MGLAP, Matrix Gla protein, NTI
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Disease relevance of MGP

  • However, OPN and MGP were expressed at sites of calcification within atherosclerotic lesions and in microvessels in calciphylaxis, suggesting that calcification in different sized vessels may occur by a common mechanism [1].
  • The aim of this study is to evaluate whether serum fetuin-A and MGP are influenced by type of renal osteodystrophy, they correlate with bone histomorphometric and histodynamic parameters, and/or serum levels may influence bone turnover [2].
  • Human vascular smooth muscle cells (VSMCs) were infected with an adenovirus carrying the MGP construct, which produced non-gamma-carboxylated MGP and fully gamma-carboxylated MGP [3].
  • Analysis of several clones thus isolated revealed that the matrix Gla protein (MGP) gene is overexpressed in the breast cancer cell line 600 PEI, though is transcribed at lower levels in most other mammary derived cultures [4].
  • This raises the possibility that MGP may be among those factors that when inhibited by vitamin K antagonists reduce metastases in experimental models [4].

Psychiatry related information on MGP

  • It is also under development by Merz, Lundbeck, Neurobiological Technologies Inc (NTI) Forest Laboratories and Suntory for the potential treatment of Alzheimer's disease (AD), AIDS-related dementia and pain in patients with neuropathy, and by Allergan for the potential treatment of ocular disease [5].

High impact information on MGP


Chemical compound and disease context of MGP


Biological context of MGP

  • Analysis of the MGP gene promoter revealed, in addition to the typical TATA and CAT boxes, the presence of a number of putative regulatory sequences homologous to previously identified hormone and transcription factor responsive elements [14].
  • The human MGP gene spans 3.9 kilobases of chromosomal DNA and consists of four exons separated by three large intervening sequences which account for more than 80% of the gene [14].
  • To characterize the genomic sequences responsible for the regulated expression of this gene, we screened a human genomic library using a MGP cDNA probe and obtained two clones containing the MGP locus [14].
  • Since chondrogenesis has been identified in calcified arteries from MPG null mice, we hypothesized that locally produced MGP might inhibit calcification by neutralizing the known effect of bone morphogenetic proteins (BMPs) as promotors of chondrogenesis and bone formation [15].
  • As the first step to test this hypothesis, we demonstrate that MGP is a binding protein for 125I-BMP-2 [15].

Anatomical context of MGP

  • The results suggest that the effects of BMP on endothelial cells occur in part through induction of ALK1, an effect that may be limited by ALK1-induced MGP [10].
  • These data show that Ca2+ and Mg2+ regulated the matrix mineralization positively and negatively, respectively, in ATDC5 cells and suggest that excess Mg2+ might inhibit the excess Ca2+-promoted mineralization mediated by MGP induction in chondrocytes [16].
  • We propose that MGP might be an important player in the adaptive homeostatic mechanism by contributing to maintain a softer trabecular meshwork tissue and facilitate aqueous humor outflow [17].
  • Thus, the endothelium, when exposed to atherogenic stimuli, ox-LDL in particular, regulates the process of calcification by enhancing the expression of the bone inhibitory MGP, while the expression of Cbfa1 remains unchanged [18].
  • In light of these results and recent information on expression of MGP gene in these same cell types in mammalian aorta, it is likely that the levels of MGP mRNA previously detected in Xenopus, birds, and mammalian heart tissue may be restricted to regions rich in smooth muscle and endothelial cells [19].

Associations of MGP with chemical compounds

  • The pattern of cartilage calcification is similar to that seen in the fetal Warfarin syndrome in humans, and may be due to abnormal synthesis of MGP [20].
  • Matrix gamma-carboxyglutamic acid protein (MGP) is a member of the vitamin K-dependent protein family with unique structural and physical properties [3].
  • MGP may be an important regulator of cartilage calcification because of its localization in cartilage and the known affinity of Gla-containing proteins for Ca2+ and hydroxyapatite [21].
  • Matrix gamma-carboxyglutamic acid (Gla)-containing protein (MGP) was found to be present in articular cartilage by Western-blot analysis of guanidinium chloride extracts of human and bovine cartilage and was further localized by immunohistochemical studies on human and monkey specimens [21].
  • Novel insights into uremic vascular calcification: role of matrix Gla protein and alpha-2-Heremans Schmid glycoprotein/fetuin [22].
  • These data demonstrate that both gamma-glutamyl carboxylation and serine phosphorylation of MGP contribute to its function as a calcification inhibitor and that MGP may inhibit calcification via binding to VSMC-derived vesicles [23].

Physical interactions of MGP


Co-localisations of MGP


Regulatory relationships of MGP

  • In addition, MGP transcripts were stimulated by extracellular calcium and downregulated by TGF-beta1 [17].
  • In contrast, BMP 4 alone had no influence on MGP or ON mRNA expression but it significantly enhanced the RA induction of MGP mRNA [26].

Other interactions of MGP

  • Depletion of ALK1 by small interfering RNA abolished the induction of MGP and VEGF [10].
  • Age-related arterial calcification may be a consequence of under-gamma-carboxylation of MGP, allowing unopposed BMP-2 activity [27].
  • BGP is synthesized only by calcified tissues while MGP is synthesized by calcified tissues, cartilage, and all soft tissues tested [20].
  • Fetuin-A, as opposed to MGP, is known to inhibit the TGF-beta/BMP complex, a protein-cytokine system that appears to be an important regulator of bone formation and probably a factor with an important role in renal osteodystrophy [2].
  • Alkaline phosphatase mRNA was absent in the preosteoblast cell lines but was induced by treatment with 10(-6) M RA, which also increased the steady-state levels of mRNA for osteopontin and BMP1. mRNA for matrix gla protein was constitutively present and further induced by RA in UMR-201 and 10B only [28].

Analytical, diagnostic and therapeutic context of MGP


  1. The involvement of matrix glycoproteins in vascular calcification and fibrosis: an immunohistochemical study. Canfield, A.E., Farrington, C., Dziobon, M.D., Boot-Handford, R.P., Heagerty, A.M., Kumar, S.N., Roberts, I.S. J. Pathol. (2002) [Pubmed]
  2. Renal osteodystrophy: alpha-Heremans Schmid glycoprotein/fetuin-A, matrix GLA protein serum levels, and bone histomorphometry. Coen, G., Ballanti, P., Balducci, A., Grandi, F., Manni, M., Mantella, D., Pierantozzi, A., Ruggeri, M., Sardella, D., Sorbo, G., Bonucci, E. Am. J. Kidney Dis. (2006) [Pubmed]
  3. Processing and transport of matrix gamma-carboxyglutamic acid protein and bone morphogenetic protein-2 in cultured human vascular smooth muscle cells: evidence for an uptake mechanism for serum fetuin. Wajih, N., Borras, T., Xue, W., Hutson, S.M., Wallin, R. J. Biol. Chem. (2004) [Pubmed]
  4. Overexpression of matrix Gla protein mRNA in malignant human breast cells: isolation by differential cDNA hybridization. Chen, L., O'Bryan, J.P., Smith, H.S., Liu, E. Oncogene (1990) [Pubmed]
  5. Memantine. Merz. Kilpatrick, G.J., Tilbrook, G.S. Current opinion in investigational drugs (London, England : 2000) (2002) [Pubmed]
  6. Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome. Munroe, P.B., Olgunturk, R.O., Fryns, J.P., Van Maldergem, L., Ziereisen, F., Yuksel, B., Gardiner, R.M., Chung, E. Nat. Genet. (1999) [Pubmed]
  7. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. Shanahan, C.M., Cary, N.R., Metcalfe, J.C., Weissberg, P.L. J. Clin. Invest. (1994) [Pubmed]
  8. Identification of a novel negative retinoic acid responsive element in the promoter of the human matrix Gla protein gene. Kirfel, J., Kelter, M., Cancela, L.M., Price, P.A., Schüle, R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  9. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Schurgers, L.J., Aebert, H., Vermeer, C., Bültmann, B., Janzen, J. Blood (2004) [Pubmed]
  10. Regulation of Bone Morphogenetic Protein-4 by Matrix GLA Protein in Vascular Endothelial Cells Involves Activin-like Kinase Receptor 1. Yao, Y., Zebboudj, A.F., Shao, E., Perez, M., Bostr??m, K. J. Biol. Chem. (2006) [Pubmed]
  11. Differential regulation of matrix Gla protein (MGP) gene expression by retinoic acid and estrogen in human breast carcinoma cells. Sheikh, M.S., Shao, Z.M., Chen, J.C., Fontana, J.A. Mol. Cell. Endocrinol. (1993) [Pubmed]
  12. The antimicrobial efficacy of 'MGP' gutta-percha in vitro. Shur, A.L., Sedgley, C.M., Fenno, J.C. International endodontic journal. (2003) [Pubmed]
  13. Clinical review 86: Euthyroid sick syndrome: is it a misnomer? Chopra, I.J. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  14. Molecular structure, chromosome assignment, and promoter organization of the human matrix Gla protein gene. Cancela, L., Hsieh, C.L., Francke, U., Price, P.A. J. Biol. Chem. (1990) [Pubmed]
  15. Modulation of the binding of matrix Gla protein (MGP) to bone morphogenetic protein-2 (BMP-2). Wallin, R., Cain, D., Hutson, S.M., Sane, D.C., Loeser, R. Thromb. Haemost. (2000) [Pubmed]
  16. Excess magnesium inhibits excess calcium-induced matrix-mineralization and production of matrix gla protein (MGP) by ATDC5 cells. Nakatani, S., Mano, H., Ryanghyok, I.M., Shimizu, J., Wada, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  17. Genes expressed in the human trabecular meshwork during pressure-induced homeostatic response. Vittitow, J., Borrás, T. J. Cell. Physiol. (2004) [Pubmed]
  18. Regulatory role of endothelium in the expression of genes affecting arterial calcification. Cola, C., Almeida, M., Li, D., Romeo, F., Mehta, J.L. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  19. Purification of matrix Gla protein from a marine teleost fish, Argyrosomus regius: calcified cartilage and not bone as the primary site of MGP accumulation in fish. Simes, D.C., Williamson, M.K., Ortiz-Delgado, J.B., Viegas, C.S., Price, P.A., Cancela, M.L. J. Bone Miner. Res. (2003) [Pubmed]
  20. Gla-containing proteins of bone. Price, P.A. Connect. Tissue Res. (1989) [Pubmed]
  21. Articular-cartilage matrix gamma-carboxyglutamic acid-containing protein. Characterization and immunolocalization. Loeser, R., Carlson, C.S., Tulli, H., Jerome, W.G., Miller, L., Wallin, R. Biochem. J. (1992) [Pubmed]
  22. Novel insights into uremic vascular calcification: role of matrix Gla protein and alpha-2-Heremans Schmid glycoprotein/fetuin. Ketteler, M., Vermeer, C., Wanner, C., Westenfeld, R., Jahnen-Dechent, W., Floege, J. Blood Purif. (2002) [Pubmed]
  23. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. Schurgers, L.J., Spronk, H.M., Skepper, J.N., Hackeng, T.M., Shanahan, C.M., Vermeer, C., Weissberg, P.L., Proudfoot, D. J. Thromb. Haemost. (2007) [Pubmed]
  24. Matrix Gla protein C-terminal region binds to vitronectin. Co-localization suggests binding occurs during tissue development. Nishimoto, S.K., Nishimoto, M. Matrix Biol. (2005) [Pubmed]
  25. Matrix GLA protein function in human trabecular meshwork cells: inhibition of BMP2-induced calcification process. Xue, W., Wallin, R., Olmsted-Davis, E.A., Borrás, T. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  26. Differential effects of transforming growth factor-beta 1 and bone morphogenetic protein 4 on gene expression and differentiated function of preosteoblasts. Zhou, H., Hammonds, R.G., Findlay, D.M., Martin, T.J., Ng, K.W. J. Cell. Physiol. (1993) [Pubmed]
  27. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. Sweatt, A., Sane, D.C., Hutson, S.M., Wallin, R. J. Thromb. Haemost. (2003) [Pubmed]
  28. Retinoic acid modulation of mRNA levels in malignant, nontransformed, and immortalized osteoblasts. Zhou, H., Hammonds, R.G., Findlay, D.M., Fuller, P.J., Martin, T.J., Ng, K.W. J. Bone Miner. Res. (1991) [Pubmed]
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