OSTEOCALCIN SYNTHESIS AND CATABOLISM

骨钙素是最丰富和彻底的特点， 骨骼中的非胶原蛋白。 虽然发现 主要在骨中，纳摩尔量可以在 血清的 血清骨钙素通常被认为是 骨形成，但我们的研究表明，其他因素， 除了其合成速率外，可能影响骨钙素 血液中的浓度。 这些问题包括：1）存在 循环中骨钙素的免疫反应片段，2） 蛋白质或其片段的肾清除率，和3）亲和力 羟磷灰石的蛋白质。 临床数据不能完全 在不了解这些因素的情况下， 测定血中骨钙素浓度。 此外还有 需要骨形成的特异性非侵入性标记物， 再吸收 通过这些研究，我们希望能够帮助 解释临床数据，并开发精确的检测方法， 代谢性骨病的诊断和治疗。 我们 提议： I. 鉴定a）体外产生的骨钙素片段 使用分离的破骨细胞，和B）体内使用灌注的大鼠 后肢 二. 研究骨钙素a）在骨水泥中的清除和催化作用 灌注的离体肝脏，和B）灌注的离体肾脏。 三. 产生针对特定区域的单克隆抗体， 蛋白 这些包括a）产生的特定片段 在骨吸收过程中，B）骨钙素原肽，其是共- 在骨钙素合成期间分泌，和c）羧基化不足 骨钙素可以在正常个体中合成， 代谢性骨病患者。 四. 开发一套有用的检测方法， 紊乱 完整骨钙素的浓度， 羧基化和羧基化不足的特异性片段，和 前肽将在a）正常个体和B） 与标准相关的代谢性骨病患者 生化和组织学参数。

Osteocalcin is the most abundant and thoroughly characterized of the non-collagenous proteins in bone. Although it is found predominantly in bone, nanomolar quantities can be measured in serum. Serum osteocalcin is generally regarded as a marker for bone formation but our studies imply that other factors, in addition to the rate of its synthesis, may affect osteocalcin concentrations in blood. These include: 1) the presence of immunoreactive fragments of osteocalcin in the circulation, 2) renal clearance of the protein or its fragments, and 3) the affinity of protein for hydroxyapatite. The clinical data cannot be fully appreciated without an understanding of the factors which determine osteocalcin's concentration in blood. In addition, there is a need for specific non-invasive markers of bone formation and resorption. Through these studies, we hope to aid in the interpretation of clinical data, and develop precise assays for use in the diagnosis and treatment of metabolic bone disorders. We propose to: I. Identify fragments of osteocalcin that are produced a) in vitro using isolated osteoclasts, and b) in vivo using perfused rat hindlimb. II. Study the clearance and catabolism of osteocalcin a) in perfused isolated liver, and b) in perfused isolated kidney. III. Produce monoclonal antibodies to specific regions of the protein. These include a) specific fragments that are produced during bone resorption, b) pro-osteocalcin peptide which is co- secreted during osteocalcin synthesis, and c) undercarboxylated osteocalcin which may be synthesized in normal individuals or in those with metabolic bone disease. IV. Develop a useful battery of assays for the evaluation of bone disorders. Concentrations of intact osteocalcin, both carboxylated and under carboxylated, specific fragments, and propeptide will be evaluated a) in normal individuals and b) in patients with metabolic bone diseases in relationship to standard biochemical and histological parameters.