Treatment with warfarin or other anticoagulants during pregnancy can lead to bone abnormalities in the fetus, the so-calledfetal warfarin syndrome, which is because of impaired synthesis of osteocalcin - a small calcium binding protein containing three y-carboxyglutamate residues found in bone matrix and dentine. It also contains a hydroxyproline residue, and thus undergoes both vitamin K- and vitamin C-dependent posttranslational modifications (Section 13.4.3). It is the most abundant of the noncollagen proteins of bone matrix, accounting for 1% to 2% of total bone protein, or 15% of noncollagen bone protein. Osteocalcin synthesis is induced by physiological concentrations of calcitriol, and the release of osteocalcin into the circulation provides a sensitive marker of vitamin D action and metabolic bone disease (Section 3.5).
Osteocalcin is synthesized in the osteoblasts as a precursor protein that then undergoes y-carboxylation of glutamate residues and cleavage of a pep-tide extension before secretion into the extracellular space, where it binds to hydroxyapatite. Osteocalcin binds to hydroxyapatite in bone and modifies the crystallization of calcium phosphates, retarding the conversion of brushite [CaHPO4.2H2O] to hydroxyapatite [Ca10(PO4)6(OH)2] and inhibiting the mineralization of bone. Osteocalcin knockout mice have a higher bone mineral density than normal. The absence of osteocalcin leads to increased bone formation without impairing resorption (Ducy et al., 1996).
The matrix Gla protein, which was originally described in bone, where it binds to both organic and mineral components, is found in a variety of tissues. It acts to prevent mineralization of cartilage and other connective tissues. Matrix Gla protein knockout mice develop a variety of abnormalities within 2 weeks of birth and die within 2 months from rupture of the aorta, associated with extensive calcification of blood vessels (Luo et al., 1997). Matrix Gla protein (atherocalcin) is also found in atherosclerotic plaque.
Nephrocalcin in the kidneys has considerable homology with matrix Gla protein. It is probably involved in renal reabsorption of calcium, but also acts to solubilize calcium salts in the urine. It is found in calcium oxalate renal stones.
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