OSTEOCALCIN SYNTHESIS AND CATABOLISM

骨钙素是最丰富和最彻底的特征 骨骼中的非胶原蛋白。尽管它被发现了 主要是在骨骼中，纳摩尔量可以在 血清。血清骨钙素通常被认为是一种标志 但我们的研究表明，其他因素，如 除其合成速度外，还可能影响骨钙素 血液中的浓度。这些包括：1)存在 循环中的骨钙素免疫反应片段，2) 蛋白质或其片段的肾清除，以及3)亲和力 用于羟基磷灰石的蛋白质。临床资料不能完整 在不了解这些因素的情况下 测定血液中骨钙素的浓度。此外，还有 需要特定的非侵入性骨形成标志物和 再吸收。通过这些研究，我们希望能够帮助 解释临床数据，并开发精确的分析方法供使用 在诊断和治疗代谢性骨病方面。我们 建议： I.鉴定在体外产生的骨钙素片段 使用分离的破骨细胞，以及b)在体内使用灌流的大鼠 后肢。 研究骨钙素a)在大鼠体内的清除和分解代谢 B)灌流离体肾。 III.产生针对特定区域的单抗 蛋白。这些包括a)产生的特定片段 在骨吸收过程中，b)骨钙素原多肽 在骨钙素合成过程中分泌，以及c)羧化不足 骨钙素可以在正常人体内合成，也可以在 那些患有代谢性骨病的人。 IV.开发一套有用的分析方法来评估骨骼 精神错乱。完整骨钙素浓度，两者 羧化和羧化下的特定片段，以及 前肽将在a)正常人和b)正常人中进行评估 代谢性骨病患者与标准的关系 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.