PARATHYROID HORMONE-OSTEOBLAST MODULATED BONE RESORPTION

甲状旁腺激素成骨细胞调节骨吸收

• 批准号: 3157139
• 负责人: HORACE M PERRY
• 金额: $ 7.83万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1988-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3157139
• 关键词: androgens; cell differentiation; dexamethasone; estrogens; extracellular matrix; hormone regulation /control mechanism; immunofluorescence technique; macrophage; monoclonal antibody; organ culture; osteoblasts; osteoclast activating factor; osteoclasts; parathyroid hormones; physiologic bone resorption; prolactin; radioimmunoassay; surface antigens; tissue /cell culture; vitamin D

Osteopenia is a major cause of morbidity and mortality in an aging population, yet its precise pathophysiology remains unclear. Since bone resorption increases as individuals age, the mechanism of control of the osteoclast, the primary resorbing cell of the skeleton, is of tremendous importance. Despite these observations, the mechanisms by which bone seeking agents, such as parathyroid hormone (PTH), activate osteoclasts are unknown. Such agents can theoretically stimulate resorption by 1) a direct interaction with osteoclasts, 2) enhancement of differentiation of osteoclast precursors or 3) interaction with an intermediary (modulator) cell which can in turn stimulate osteoclastic activity and/or promote osteoclast differentiation. Available evidence suggests that parathyroid hormone enhances resorption via modulator cells. We propose that osteoblasts have the capacity to modulate parathyroid hormone induced bone absorption because 1) they produce agents which stimulate osteoclasts, 2) osteoblasts bind parathyroid hormone and are responsive to the hormone and 3) bone resorption by isolated macrophages (surrogate osteoclasts) is not stimulated by the PTH unless osteoblasts are also present. This proposal is directed toward examining the mechanisms by which parathyroid hormone stimulates osteoblast modulated bone resorption. The initial studies will address the isolation of the factor produced by osteoblasts in response to parthyroid hormone which is capable of increasing bone resorption. Other studies will address the mechanisms by which this effect takes place both at a biochemical and cellular level. The studies will also address the modulation of this response in osteoblasts by other hormones as well as the modulation of the response of the resorbing cell. These experiments will focus on the properties of the various cell types which are known to enhance their capacity to degrade bone matrix. These properties include a) enhance differentiation of immature macrophages, b) enhancement of the capacity of resorptive macrophages to bind the bone, c) enhanced multinucleation of macrophages and d) increased macrophage number.

骨质减少是老年人发病和死亡的主要原因 人群，但其确切的病理生理学仍不清楚。 自从bone 随着年龄的增长，再吸收增加， 破骨细胞是骨骼的主要吸收细胞， 重要性 尽管有这些观察结果，骨骼 寻求代理人，如甲状旁腺激素（PTH），激活破骨细胞， 未知 这些试剂理论上可以通过以下方式刺激再吸收：1）直接 与破骨细胞的相互作用，2）增强 破骨细胞前体或3）与中间体（调节剂）的相互作用 其又可以刺激骨细胞活性和/或促进 破骨细胞分化 现有证据表明，甲状旁腺 激素通过调节细胞增强再吸收。 我们建议 成骨细胞具有调节甲状旁腺激素诱导的骨形成的能力 吸收，因为1）它们产生刺激破骨细胞的试剂，2） 成骨细胞结合甲状旁腺激素并对该激素有反应， 3)分离的巨噬细胞（替代破骨细胞）的骨吸收不是 由PTH刺激，除非成骨细胞也存在。 这项建议 旨在研究甲状旁腺激素 刺激成骨细胞调节的骨吸收。 初步研究将 解决成骨细胞响应于以下产生的因子的分离： 甲状旁腺激素，能够增加骨吸收。 其他 研究将解决这种效应发生的机制， 在生物化学和细胞水平上。 这些研究还将探讨 成骨细胞的这种反应受到其他激素的调节， 调节再吸收细胞的反应。 这些实验将 集中在已知的各种细胞类型的属性， 增强其降解骨基质的能力。 这些属性包括a） 增强未成熟巨噬细胞的分化，B）增强未成熟巨噬细胞的分化， 吸收性巨噬细胞结合骨的能力，c）增强 巨噬细胞的多核化和d）增加巨噬细胞数量。