PARATHYROID HORMONE LYMPHOCYTE AND BONE RESORPTION

破骨细胞是骨骼的主要吸收细胞，但 甲状旁腺激素(PTH)等寻骨剂的作用机制 激活这个细胞是未知的。从理论上讲，这类药物可以刺激 通过1)与破骨细胞直接相互作用，2)促进骨吸收 破骨细胞前体的分化，或3)与血管内皮生长因子的相互作用 中介(调节器)细胞，可反过来刺激破骨细胞 激活和/或促进破骨细胞分化。现有证据 提示甲状旁腺激素不直接与破骨细胞或其 前驱物质，因此可能通过调制器增强吸收 细胞。我们认为淋巴细胞具有调节能力 甲状旁腺激素诱导的骨吸收，因为1)它们产生一种物质(S)(破骨细胞 激活因子)刺激破骨细胞，2)淋巴细胞结合甲状旁腺素 对激素有反应，以及3)通过分离的骨吸收 巨噬细胞(代理破骨细胞)不受甲状旁腺素刺激，除非 淋巴细胞也存在。这项建议旨在研究 甲状旁腺激素刺激淋巴细胞增强的机制 巨噬细胞介导的骨吸收。初步研究将针对 A)时间进程，b)事件的剂量依赖性，c)PTH是否诱导 淋巴细胞的原始转化，d)是否短期 淋巴细胞与甲状旁腺素预先孵育诱导这些细胞刺激 巨噬细胞介导的吸收，以及e)其他激素的相互作用 甲状旁腺素在调节MO介导的吸收中起作用。接下来我们将评估 巨噬细胞暴露时的生理变化 至甲状旁腺素刺激的淋巴细胞。这些实验将重点放在属性上 已知可增强其降解骨骼能力的巨噬细胞 矩阵。这些特性包括：a)未成熟细胞的分化增强 巨噬细胞，b)增强吸收巨噬细胞的能力 与骨结合，c)增强巨噬细胞的多核，d)增加 巨噬细胞数。最后，我们建议对生物化学进行表征。 甲状旁腺素刺激的淋巴细胞产生因子(S)的性质 促进巨噬细胞的骨吸收。

The osteoclast is the primary resorbing cell of the skeleton, but the mechanisms by which bone-seeking agents, such as parathyroid hormone (PTH), activate this cell 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 osteoclast activity and/or promote osteoclast differentiation. Available evidence suggests that PTH does not directly interact with osteoclasts or their precursors and is therefore likely to enhance resorption via modulator cells. We propose that lymphocytes have the capacity to modulate PTH-induced bone resorption because 1) they produce an agent(s) (osteoclast activating factor) which stimulates osteoclasts, 2) lymphocytes bind PTH and are responsive to the hormone, and 3) bone resorption by isolated macrophages (surrogate osteoclasts) is not stimulated by PTH unless lymphocytes are also present. This proposal is directed towards examining the mechanisms by which PTH-stimulated lymphocytes enhance macrophage-mediated bone resorption. The initial studies will address the a) time course, b) dose dependency of the event, c) whether PTH induces blast transformation in lymphocytes, d) whether a short period of preincubation of lymphocytes with PTH induces these cells to stimulate macrophage-mediated resorption, and e) the interaction of other hormones with PTH in modulating MO-mediated resorption. We will next evaluate the alterations of macrophage physiology which occur when the cells are exposed to PTH-stimulated lymphocytes. These experiments will focus on properties of macrophages which are known to enhance their capacity to degrade bone matrix. These properties include a) enhanced differentiation of immature macrophages, b) enhancement of the capacity of resorptive macrophages to bind to bone, c) enhanced multinucleation of macrophages, and d) increased macrophage number. Finally, we propose to characterize the biochemical properties of the putative PTH-stimulated lymphocyte-produced factor(s) which promote bone resorption by macrophages.