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Published 7 June 2004. doi:10.1083/jcb.200402046
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 5, 625-630
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Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins



Monzur Murshed1,2, Thorsten Schinke1, Marc D. McKee3,4, and Gerard Karsenty1,2

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030
2 Bone Disease Program of Texas, Baylor College of Medicine, Houston, TX 77030
3 Faculty of Dentistry, McGill University, Montreal, Quebec, Canada H3A 2B2
4 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada H3A 2B2

Address correspondence to Gerard Karsenty, Baylor College of Medicine, One Baylor Plaza, Rm. S921, Houston, TX 77030. Tel.: (713) 798-5489. Fax: (713) 798-1530. email: karsenty{at}bcm.tmc.edu

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 {gamma}-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.

Key Words: MGP; osteocalcin; ECM; mineralization; local regulation

Abbreviations used in this paper: ECMM, ECM mineralization; MGP, matrix gla protein; VSMC, vascular smooth muscle cell; WT, wild-type.


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