OSTEOCALCIN SYNTHESIS AND CATABOLISM

描述（改编自申请人摘要）：骨的使用 临床研究中的标志物提供了重要的见解， 生理过程和治疗信息， 代谢性骨病 骨钙素是研究最广泛的 骨转换的生物标志物，它通常被认为是一种 成骨细胞活性指数。 然而，临床解释的一个 个体患者的骨钙素测量通常是不明确的， 并不总是与其他标志物或临床发现相关。 这些 由于测定特异性的差异而产生困难， 关于蛋白质循环形式起源的不确定性， 对它在骨骼中的功能缺乏清楚的了解。 的研究 申请人实验室证明除了完整的蛋白质， 在循环中发现骨钙素的片段。 他们已经确定 通过使用具有特异性表位的抗体， 这些骨钙素的单个片段可能由成骨细胞产生 和/或破骨细胞，并可能反映不同的细胞过程有关， 骨钙素在骨中的作用。 有鉴于此，建议 实验旨在回答以下问题：（1）什么是 骨钙素在血液循环中的形式 建议努力 通过使用特异性抗体进一步鉴定骨钙素的循环形式， 免疫测定结合HPLC和质谱分析。 计划 实验将鉴定和定量血清中的这些形式（a）， 正常成人和儿童，就年龄、种族和性别而言，和（B）在 代谢性骨病患者。 将比较结果值 标准临床测量，包括促钙激素，矿物质， 骨吸收和骨密度的标志物;（2）骨吸收的来源是什么？ 循环骨钙素 申请人将研究（a）骨钙素 生物合成，使用成骨细胞的原代培养物，（B） 骨钙素，在骨吸收系统中使用兔源性破骨细胞， 和c）主要碎片的代谢清除;和（3）什么是 骨钙素在骨中的作用 在这里，骨钙素的潜在作用， 骨转换和钙稳态将通过研究 骨钙素缺乏小鼠对急性和慢性矿物质和 荷尔蒙变化 响应性将由标准决定 钙稳态的测量，包括促钙激素，矿物质， 骨吸收标志物，骨形成的替代测量，骨 骨密度、骨组织形态计量学、骨矿物质质量和含量。

DESCRIPTION (Adapted from the Applicant's Abstract): The use of bone markers in clinical studies has provided both important insights into physiological processes, and information on therapy for the treatment of metabolic bone disease. Osteocalcin is one of the most extensively studied biological markers of bone turnover, and it is generally regarded as an index of osteoblastic activity. However, the clinical interpretation of an osteocalcin measurement in individual patients is often ambiguous and does not always correlate with other markers, or with clinical findings. These difficulties arise because of differences in assay specificity, uncertainties regarding the origin of the circulating forms of the protein, and lack of a clear understanding of its function in bone. Studies in the applicant laboratory demonstrate that in addition to the intact protein, fragments of osteocalcin are found in the circulation. They have identified several of these fragments by the use of antibodies with specific epitopes. These individual fragments of osteocalcin may be produced by osteoblasts and/or osteoclasts, and may reflect distinct cellular processes related to the function of osteocalcin in bone. In light of this, the proposed experiments are designed to answer the following questions: (1) what are the forms of osteocalcin in the circulation? Efforts are proposed to further identify the circulating forms of osteocalcin by using specific immunoassays coupled with HPLC and mass spectral analysis. The planned experimentation will identify and quantitate these forms (a) in serum from normal adults and children, with respect to age, race, and sex, and (b) in patients with metabolic bone disease. The resultant values will be compared to standard clinical measures, including calcitropic hormones, minerals, markers of bone resorption, and bone density; (2) what is the source of circulating osteocalcin? The applicants will study (a) osteocalcin biosynthesis, using primary cultures of osteoblasts, (b) the catabolism of osteocalcin, using rabbit-derived osteoclasts in a bone resorbing system, and c) metabolic clearance of the major fragments; and (3) what is the function of osteocalcin in bone? Here, the potential role of osteocalcin in bone turnover and calcium homeostasis will be examined by studying the response of osteocalcin-deplete mice to acute and chronic mineral and hormonal alterations. Responsiveness will be determined by standard measures of calcium homeostasis, including calcitropic hormones, minerals, markers of bone resorption, alternative measures of bone formation, bone density, histomorphometry, and mineral quality and content in bone.