GLUCOCORTICOID ACTIONS ON OSTEOCLASTS

慢性炎症反应发生在牙周病 经常由于牙槽骨的破坏而导致牙齿脱落。 这种破坏很可能部分是破骨细胞的结果 由慢性炎症细胞产生的细胞因子刺激。 在 成年后，正常的骨代谢涉及破骨细胞- 介导的吸收和成骨细胞介导的形成。 这种平衡， 称为耦合，导致整体骨无净变化 在成年生活中。 大多数与骨骼系统有关的疾病 例如感染性（牙周病）、代谢性（骨关节炎） 骨质疏松症、肾性骨营养不良、佩吉特）、遗传性（骨生成 骨肉瘤、骨硬化）和肿瘤（骨肉瘤、巨细胞 肿瘤），涉及吸收-形成偶联的异常。 骨 再吸收率是由两个数量和活动水平， 破骨细胞 许多激素信号可能影响破骨细胞 招募、分化和/或直接或 间接地。 临床上，糖皮质激素治疗类风湿 关节炎改善牙周组织的健康，但是，矛盾的是， 治疗通常导致糖皮质激素诱导的骨质疏松症。 的 糖皮质激素影响骨代谢的机制尚不清楚 明白 有许多关于成骨细胞对 糖皮质激素治疗，但研究糖皮质激素的影响， 骨吸收显示出相反的结果。 在此提交的证据 应用表明，高度纯化的破骨细胞含有 糖皮质激素受体和糖皮质激素调节破骨细胞 骨吸收 拟议研究的目的是验证 糖皮质激素对破骨细胞骨吸收的直接影响， 来识别这种反应的一些细胞效应器。 的 这些研究的具体目标是：1）识别和定量 鸟类破骨细胞和人类巨细胞瘤中的糖皮质激素受体 （破骨细胞瘤），2）定量和表征 糖皮质激素对破骨细胞吸收活性的影响，3）分析 糖皮质激素对破骨细胞核原癌基因影响 4）评估糖皮质激素对破骨细胞的影响 核原癌基因表达，4）评估 糖皮质激素对选定破骨细胞蛋白基因表达的影响， 与吸收过程有关 分离的禽类 破骨细胞和人破骨细胞瘤将用于表征 破骨细胞糖皮质激素受体 此外，鸟类破骨细胞和 人成骨细胞瘤培养物将用糖皮质激素激发， 研究糖皮质激素对骨吸收及基因的影响 体外反应。

The chronic inflammatory response which occurs during periodontal disease often results in tooth loss due to the destruction of alveolar bone. This destruction is likely, in part, to be the result of osteoclast stimulation by cytokines produced by the chronic inflammatory cells. In adult life, normal bone metabolism involves a balance between osteoclast- mediated resorption and osteoblast-mediated formation. this balance, referred to as coupling, results in no net change in overall bone throughout adult life. Most diseases relating to the skeletal system such as infectious (periodontal disease), metabolic (osteoarthritis, osteoporosis, renal osteodystrophy, Paget's), inherited (osteogenesis imperfecta, osteopetrosis), and tumor-based (osteosarcoma, giant cell tumor), involve abnormalities in the resorption-formation coupling. Bone resorption rates are determined by both the number and activity level of osteoclasts. A number of hormonal signals may influence osteoclast recruitment, differentiation, and/or activity either directly or indirectly. Clinically, glucocorticoid treatment for rheumatoid arthritis improves the health of periodontal tissue, but, paradoxically, treatment often results in glucocorticoid-induced osteoporosis. The mechanism by which glucocorticoids influence bone metabolism are not well understood. There are numerous reports of osteoblast responses to glucocorticoid treatments, but studies on glucocorticoid influences on bone resorption have shown opposing results. Evidence presented in this application suggests that highly purified osteoclasts contain glucocorticoid receptors and that glucocorticoids regulate osteoclast bone resorption. The objectives of the proposed studies are to verify the direct influence of glucocorticoids on osteoclast bone resorption and to identify some of the cellular effectors of this response. The specific aims of these studies are to: 1) identify and quantitate glucocorticoid receptors in avian osteoclasts and human giant cell tumors (osteoclastomas), 2) quantitate and characterize the effect of glucocorticoids on osteoclast resorption activity, 3) analyze the influence of glucocorticoids on osteoclast nuclear proto-oncogene expression and, 4) assess the influence of glucocorticoids on osteoclast nuclear proto-oncogene expression and, 4) assess the influence of glucocorticoids on gene expression of selected osteoclast proteins which have been implicated in the resorption process. Isolated avian osteoclasts and human osteoclastomas will be used to characterize osteoclast glucocorticoid receptors. In addition, avian osteoclast and human osteoclastoma cultures will be challenged with glucocorticoids to study the influence of glucocorticoids on bone resorption and gene responses in vitro.