Osteocalcin Synthesis and Catabolism

描述(申请人提供)：维生素K参与各种蛋白质的生理激活，这些蛋白质与止血、骨和软骨代谢有关。骨钙素是一种维生素K依赖的钙结合蛋白，存在于骨和牙本质的有机基质中。循环骨钙素是一种高度特异的成骨细胞标志物，已被广泛用于评价骨转换。这里提出的研究试图验证骨钙素或其片段作为维生素K状态和骨转换指标的新方法。这些研究将评估：(1)骨钙素片段的循环水平与钙动力学的骨吸收和吸收之间的关系；(2)维生素K摄入对骨钙素循环形式的影响及其与其他骨转换指标的相关性。虽然，骨钙素的功能还没有被准确地定义，但在小鼠身上的研究表明，骨钙素可能在骨重建中发挥作用。拟议的研究将(1)用一种未羧化的变体拯救骨钙素缺失的小鼠(OC-/-)，使骨钙素不会在骨骼中积聚，但循环水平将会提高。通过骨密度、矿物质含量、骨转换标志物、组织形态计量学参数和破骨细胞发育来评估1，25(OH)2D3和去卵巢对WT、OC-/-和被救治动物的影响。破骨细胞和/或成骨细胞前体细胞将在骨髓细胞中进行评估。

DESCRIPTION (provided by applicant): Vitamin K is involved in the physiological activation of various proteins involved in hemostasis and bone and cartilage metabolism. Osteocalcin is a vitamin K-dependent Ca2+binding protein found in the organic matrix of bone and dentin. Circulating osteocalcin is a highly specific osteoblastic marker and it has been widely used for assessing bone turnover. The studies proposed here seek to verify new methods for the measurement of osteocalcin or its fragments as indicators of vitamin K status and bone turnover. These studies will evaluate: (1) the relationship between circulating levels of osteocalcin fragments and bone accretion and resorption via calcium kinetics; and (2) the effect of vitamin K intake on the profile of circulating forms of osteocalcin and their correlation with other measures of bone turnover. Although, the function of osteocalcin has not been precisely defined, studies in mice suggest that osteocalcin may play a role in bone remodeling. The proposed studies will (1) rescue the osteocalcin null mouse (OC-/-) with an uncarboxylated variant such that osteocalcin will not accumulate in bone but circulating levels will be elevated. The effects of 1,25(OH)2D3 and ovariectomy in wt, OC-/- and rescued animals will be evaluated by bone density, mineral content, bone turnover markers histomorphometric parameters and osteoclast development. Osteoclast and/or osteoblast progenitors will be evaluated in bone marrow cells.