PARATHYROID HORMONE-OSTEOBLAST MODULATED BONE RESORPTION

骨量减少是老年人发病和死亡的主要原因。 然而，其确切的病理生理学仍不清楚。自骨 随着个体年龄的增长，吸收增加，控制 破骨细胞是骨骼的主要吸收细胞，具有巨大的 重要性。尽管有这些观察，骨骼 寻找药物，如甲状旁腺激素(PTH)，激活破骨细胞 未知。从理论上讲，这种药剂可以通过1)直接的 与破骨细胞的相互作用，2)促进分化 破骨细胞前体或3)与中间体(调节物)的相互作用 细胞反过来可以刺激破骨细胞活动和/或促进 破骨细胞分化。现有证据表明甲状旁腺 荷尔蒙通过调节细胞促进吸收。我们建议 成骨细胞具有调节甲状旁腺激素诱导的骨的能力 吸收是因为1)它们产生刺激破骨细胞的物质，2) 成骨细胞结合甲状旁腺激素，并对激素和 3)分离的巨噬细胞(代理破骨细胞)的骨吸收不是 由甲状旁腺素刺激，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 解决分离成骨细胞产生的因子以响应 甲状旁腺激素，能够增加骨吸收。其他 研究将探讨这种效应发生的机制 在生化和细胞水平上。这些研究还将涉及 其他激素对成骨细胞这一反应的调节作用 调节吸收细胞的反应。这些实验将 关注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) 促进未成熟巨噬细胞的分化，b)增强 吸收巨噬细胞与骨结合的能力，c)增强 巨噬细胞多核；d)巨噬细胞数量增加。

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.