Mineralization osteocalcin

In bone, three proteins have been described which are vitamin K-dependent, osteocalcin (bone Gla protein), matrix Gla protein (MGP), and protein S. Osteocalcin is synthetized by osteoclasts, regulated by the active form of vitamin D, calcitriol. Its capacity to bind calcium needs a vitamin K-dependent y-carboxylation of three glutamic acid residues. The calcium binding capacity of osteocalcin indicates a possible role in bone mineralization, but its exact function is still unclear. However, it is widely used as a serum marker for bone mineralization. Protein S, mainly a coagulant, is also vitamin-K dependent and synthesized in the liver. Children with... 

There are approximately 200 other proteins present in bone, though most of them are present only in trace amounts (Delmas et al., 1984 Linde et al., 1980, as cited in van Klinken, 1991). The second most common bone protein, osteocalcin, comprises 1-2 weight % of total fresh bone. Osteocalcin bonds with both the bone mineral fraction and bone collagen, but it seems to be unstable in solutions. Due to its small molecular size and strong mineral stabilization, osteocalcin can survive up to 50.000 years (C.l. Smith et al., 2005), and it may offer an alternative to the use of collagen in paleoenvironmental stable isotope research. However, osteocalcin s role and importance in this field of study has yet to be defined (Collins et al., 2002). 

Williams DC, Paul DC, Black LJ (1991) Effects of estrogen and tamoxifen on serum osteocalcin levels in ovariectomized rats. Bone Miner 14 205-220... 

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... 

Glucocorticoids can even cause osteoporosis when they are used for long-term replacement therapy in the Addison s disease, as has been shown by a study of 91 patients who had taken glucocorticoids for a mean of 10.6 years, in whom bone mineral density was reduced by 32% compared with age-matched controls (SEDA-19, 377 198). However, these results contrasted with the results of a Spanish study in patients with Addison s disease, in which no direct relation was found between replacement therapy and either bone density or biochemical markers of bone turnover of calcium metabolism (alkaline phosphatase, osteocalcin, procollagen I type, parathormone, and 1,25-dihydroxycolecalciferol) (SEDA-19, 377 199). 

The effects of inhaled glucocorticoids on bone mineral density (measured using dual X-ray absorptiometry of the spine and hip) and biochemical parameters were followed over 18 months. Mean serum osteocalcin concentrations were significantly lower in patients taking beclomethasone dipropionate or budesonide at doses of 800 micro-grams/day and more. However, bone mineral density of the lumbar spine and hip was not affected. The normal advancement of bone mineral density expected in growing children was not affected by inhaled glucocorticoids taken for 7-16 months (SEDA-22,184). 

In a 12-month, multicenter comparison of fluticasone propionate 250-500 micrograms/day with beclomethasone dipropionate 500-1000 micrograms/day, the two drugs had an equal therapeutic effect. Fluticasone propionate treatment resulted in a higher bone mineral density (assessed at the hip) and higher serum osteocalcin concentrations. 

In a prospective randomized comparison of the effects of fluticasone propionate 1000 micrograms/day and budesonide 1600 micrograms/day, over 1 year, bone mineral density measured in the spine was normal at the start of the study and increased slightly with time in both groups, as did serum osteocalcin concentration. 

A 2-year randomized controlled study in 90 women compared the effects of oral tibolone doses of 1.25 mg/day and 2.5 mg/day on bone loss in the early postmenopausal period all took calcium 1000 mg/day. Vertebral and femoral bone density rose in both treated groups but fell in the control group, and bone turnover markers (urinary excretion of hydroxyproline/creatinine and plasma osteocalcin concentrations) were similarly affected favorably in the treated groups, as was the incidence of hot flushes/ flashes (5). Studies such as this still leave open the question of the advisability of continuing tibolone treatment over a longer period. While tibolone has indeed been shown to benefit mineral bone density, few data are available to show whether it lowers fracture incidence nor is it clear whether there is a link between tibolone and breast cancer (6). 

Bradbeer, J. N., Virdi, A. S., Serre, C. M., Beresford, J. N., Delmas, P. D., Reeve, 1., and Triffitt, 1. T. 1994. A number of osteocalcin antisera recognize epitopes on proteins other than osteocalcin in cultured skin fibroblasts Implications for the identification of cells of the osteoblastic lineage in vitro. J. Bone Miner. Res. 9 1221-1228. 

Figure 11.3 Studies in mutant mice, (a) Image of mineral to matrix in the growth plate of a young mouse lacking matrix gla protein (MGP—/—) and its wildtype control (MGP+/+). Note the gradient of mineral matrix ratios in the wildtype is not apparent in the knockout, (b) Mineral matrix increases at three sites in the cortices of the osteocalcin knockout (KO) mouse (6 month data), while crystallinity is decreased relative to wildtype (WT) controls, (c) In the osteonectin knockout mouse (4 months old) the collagen maturity assessed in terms of the 1660 1690 peak area ratio is increased on the periosteal and endosteal surface.

Bone sialoprotein, osteopontin, and osteocalcin are synthesized and deposited as the mineralization process begins and mineral nodules form (Stein and Lian, 1993). Bone sialoprotein contains the cell-adhesive arginine-glycine-aspartic acid peptide sequence and may thus mediate osteoblast adhesion on the extracellular matrix (Gehron-Robey, 1989). Osteocalcin, a calcium-binding protein, interacts with hydroxyapatite and is thought to mediate coupling of bone resorption (by osteoclasts) and bone formation (by osteoblasts and/or osteocytes) (Stein and Lian, 1993). 

G2. Garnero, P., Grimaux, M., Seguin, P., and Delmas, P. D., Characterization of immunoreactive forms of human osteocalcin generated in vivo and in vitro. J. Bone Miner Res. 9,255-264 (1994). 

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