Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins

Abstract

Extracellular matrix mineralization (ECMM) is a physiologic process in the skeleton and in teeth and a pathologic one in other organs. The molecular mechanisms controlling ECMM are poorly understood. Inactivation of Matrix gla protein (Mgp) revealed that MGP is an inhibitor of ECMM. The fact that MGP is present in the general circulation raises the question of whether ECMM is regulated locally and/or systemically. Here, we show that restoration of Mgp expression in arteries rescues the arterial mineralization phenotype of Mgp−/− mice, whereas its expression in osteoblasts prevents bone mineralization. In contrast, raising the serum level of MGP does not affect mineralization of any ECM. In vivo mutagenesis experiments show that the anti-ECMM function of MGP requires four amino acids which are γ-carboxylated (gla residues). Surprisingly, another gla protein specific to bone and teeth (osteocalcin) does not display the anti-ECMM function of MGP. These results indicate that ECMM is regulated locally in animals and uncover a striking disparity of function between proteins sharing identical structural motifs.

Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification

“…Indication that such transformations could take place in the aortic wall has been provided by Watson et al (11) who showed that a subpopulation of cultured VSMCs were transformed to calcifying vascular cells (CVCs) capable of forming a mineralized matrix. We have shown (12) that BMP-2 and MGP are both synthesized by VSMCs and Murshed et al (13) have shown that MGP synthesized in the vessel wall and not blood born MGP is the in vivo pool of the protein that is active as the vascular calcification inhibitor. These findings emphasize the importance to understand the MGP-BMP-2 interaction in inhibition of vascular calcification.…”

Vanin-1 Pantetheinase Drives Increased Chondrogenic Potential of Mesenchymal Precursors in ank/ank Mice

“…The ank/ank mice failed to thrive. 3,8,11,12 However, there was no significant difference in body weight of 10 male mice of each geno- Figure 7. Correction of increased calcification of ank/ank aortic ring explants and cultured SMCs by Vanin-1 gene knockout.…”

“…[1][2][3][4] Heritable deficiencies in mineralization regulators have been particularly informative about hierarchical, co-operative, and antagonistic relationships among such factors. 2,5,6 Indeed, the particularly potent capacity of PP i to inhibit hydroxyapatite crystal growth 7 has been underscored by the phenotypic effects of alteration of PP i transport and generation.…”

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

“…In the vascular wall, the inhibition of γ-carboxylation of Glu residues yielded the undercarboxylation of MGP and the subsequent calcification of the tunica media [10]. Moreover, it has been shown in the bone tissue of transgenic mice, which produced two distinct mutated forms of MGP in osteoblasts, that the Gla residues are required for MGP antimineralization function [21].…”