Vitamin osteocalcin synthesis

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 concenUations 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). 

Cholestasis-linked osteopathy (M. Loeper et al., 1939), which occurs much more frequently in the form of osteoporosis than osteomalacia, can be expected in up to 50% of cases. The pathogenesis is complex. Vitamin D status can be examined by determining 25-OH-cholecal-ciferol in the serum. Intestinal calcium loss and reduced calcium absorption due to vitamin D deficiency are key pathogenetic factors. It is still a matter of debate whether vitamin K deficiency (which can lead to reduced osteocalcin synthesis) and deficiencies in IGF I and II (which can cause dysfunction of the osteoblasts) are possible causes of this condition. Muscle and bone pain are frequent clinical symptoms, occurring mainly in the wrists and ankles. 

Yamamoto T., Ozono K., Shima M., Yamaoka K. and Okada S. 1998. 24R,25-dihydroxyvitamin D3 increases cyclic GMP contents, leading to an enhancement of osteocalcin synthesis by 1,25-dihydroxy vitamin D3 in cnltured hnman osteoblastic cells. Exp. Cell Res. 244 71-6. 

Treatment of pregnant women with warfarin can lead to fetal bone abnormalities (fetal warfarin syndrome). Two proteins are present in bone that contain y-carboxygluta-mate, osteocalcin and bone matrix Gla protein. Osteocalcin also contains hydroxyproHne, so its synthesis is dependent on both vitamins K and C in addition, its synthesis is induced by vitamin D. The release into the circulation of osteocalcin provides an index of vitamin D stams. 

A number of iron-containing, ascorbate-requiring hydroxylases share a common reaction mechanism in which hydroxylation of the substrate is linked to decarboxylation of a-ketoglutarate (Figure 28-11). Many of these enzymes are involved in the modification of precursor proteins. Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen to collagen, and prohne hydroxylase is also required in formation of osteocalcin and the Clq component of complement. Aspartate P-hydroxylase is required for the postsynthetic modification of the precursor of protein C, the vitamin K-dependent protease which hydrolyzes activated factor V in the blood clotting cascade. TrimethyUysine and y-butyrobetaine hydroxylases are required for the synthesis of carnitine. 

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

The physiological role of vitamin K is in blood clotting and is essential for the synthesis of at least four of the proteins (including prothrombin) involved in this process. Vitamin K also plays a role in the synthesis of a protein (osteocalcin) in bone. Vitamin K deficiency is rare but can result from impaired absorption of fat. Vitamin K levels in the body are also reduced if the intestinal flora is killed (e.g. by antibiotics). Vitamin K toxicity is rare but can be caused by excessive intake of vitamin K supplements. Symptoms include erythrocyte haemolysis, jaundice, brain damage and reduced effectiveness of anticoagulants. 

Warfarin is a poison that inhibits the action of vitamin K by preventing gla residue synthesis (Sect. 11.2.2) and therefore causes an osteocalcin deficiency. Mice in which the... 

In bone, a CaBP called osteocalcin contains 49 amino acids (M.W. 5500-6000). Its synthesis is stimulated by 1,25-(0H)2D. Osteocalcin contains four residues of y-carboxyglutamic acid, which require vitamin K for their synthesis and are important as binding sites for calcium (Chapter 36). Although vitamin K deficiency reduces the osteocalcin content of bone, it does not cause functional bone defects. For this reason, osteocalcin may function in calcium mobilization rather than deposition. Alternatively, as an effective inhibitor of hydroxyapatite formation, it may prevent overmineralization of bone. 1,25-(OH)2D increases y-glutamyl carboxylase activity in the renal cortex. The relationship between vitamin D and vitamin K needs clarification. 

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