Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins.
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.
Murshed
Monzur
M
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. S921, Houston, TX 77030, USA.
Schinke
Thorsten
T
McKee
Marc D
MD
Karsenty
Gerard
G
D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000503:physiopathology; D002113:Calcification, Physiologic / Q000502:physiology*; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D015675:Osteocalcin / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics; D000097568:Matrix Gla Protein
D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D015675:Osteocalcin; D000097568:Matrix Gla Protein