GLUOCORTICOIDS, OSTEOCYTES, AND BONE STENGTH IN AGE-RELATED OSTEOPOROSIS

基于这一发现，糖皮质激素导致的骨强度丧失部分是由于 骨细胞的死亡与骨丢失无关，并且有证据表明皮质醇水平以及局部组织 在小鼠和人类中，糖皮质激素作用的放大都随着年龄的增长而增加，假设 随着年龄增长而出现的骨强度和骨量之间的差异，部分是由于不利的骨骼。 内源性糖皮质激素的影响将得到测试。糖皮质激素作用的这种增强将 导致骨细胞凋亡率增加，破骨细胞寿命延长。 糖皮质激素对这些细胞的作用是由富含Pro的酪氨酸的非遗传性机制引起的 蛋白激酶2(PYK2)激活。随后糖皮质激素诱导的骨细胞凋亡对骨产生负面影响 通过扰乱管状循环、降低材料性能、允许积累 骨头受损，或者三处都有。为了验证这一假设，在目标1中，体内对比骨丢失和 野生型和转基因小鼠8、16和25个月龄时的骨密度和强度 过表达113-羟基类固醇脱氢酶2，一种使糖皮质激素失活的酶 前受体的时尚，将会被决定。这将在 骨钙素启动子(从而保护骨细胞和成骨细胞免受糖皮质激素的作用)或 抗酒石酸酸性磷酸酶启动子的控制(从而保护破骨细胞免受糖皮质激素的影响 操作)。在目标2中，焦点黏附相关蛋白PYK2在反式作用中的作用 糖皮质激素对骨细胞和破骨细胞寿命的影响将被描绘出来。具体地说，那些相反的影响 有诱导骨细胞凋亡和预防破骨细胞凋亡的作用。在目标3中，贡献 骨细胞凋亡对骨强度的影响将通过诱导快速、有条件的骨细胞消融来确定 通过白喉毒素和牙本质基质蛋白1启动子控制的细胞凋亡 小鼠的白喉毒素受体，一种对白喉毒素不敏感的物种。创新研究 在这个项目中提出的将通过描绘内源的贡献来扩展先前的工作 糖皮质激素对影响骨骼老化的多因素损伤。这个项目的重要性在于 随着美国老龄化，骨质疏松症的负担将日益加重。老年人 对糖皮质激素对骨骼的不利影响更加敏感，这个项目将提供详细的 肾上腺分泌的糖皮质激素在老年人骨折中的作用 骷髅。

Based on the discovery that glucocorticoid-induced loss of bone strength results in part from increased death of osteocytes independent of bone loss, and evidence that cortisol levels as well as local tissue amplification of glucocorticoid action increase with age in both mice and humans, the hypothesis that the disparity between bone strength and mass that occurs with aging is due in part to the adverse skeletal impact of endogenous glucocorticoids will be tested. This enhancement of glucocorticoid effects would result in an increase in the prevalence of osteocyte apoptosis and prolongation of osteoclast lifespan. Glucocorticoid effects on these cells result from nongenotropic mechanisms involving proline-rich tyrosine kinase 2 (Pyk2) activation. The ensuing glucocorticoid-induced osteocyte apoptosis negatively affects bone strength by disrupting canalicular circulation, degrading material properties, allowing accumulation of damaged bone, or all three. To test this hypothesis, in Aim 1, the contrast in vivo between the loss of bone mineral density (BMD) and strength at 8, 16, and 25 months of age in wild-type and transgenic mice overexpressing 113-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids in a pre-receptor fashion, will be determined. This will be accomplished either under the control of the osteocalcin promoter (thus protecting osteocytes and osteoblasts from glucocorticoid action) or under control of the tartrate-resistant acid phosphatase promoter (thus protecting osteoclasts from glucocorticoid actions). In Aim 2, the role of the focal adhesion-related protein Pyk2 in the opposing effects of glucocorticoids on osteocyte and osteoclast lifespan will be delineated. Specifically, those opposing effects are the induction of osteocyte apoptosis and prevention of osteoclast apoptosis. In Aim 3, the contribution of osteocyte apoptosis to bone strength will be determined by inducing rapid, conditional osteocyte ablation via apoptosis using diphtheria toxin administration and the dentin matrix protein 1 promoter controlling the diphtheria toxin receptor in mice, an otherwise diphtheria toxin-insensitive species. The innovative studies proposed in this project will extend previous work by delineating the contribution of endogenous glucocorticoids to the multifactorial damages that affect the aging skeleton. The importance of this project is amplified by the increasing burden of osteoporosis that will occur with the aging of America. Older people are more sensitive to the adverse skeletal effects of glucocorticoids and this project will provide a detailed investigation of how the glucocorticoids produced by their adrenal glands contribute to fractures in the agjng skeleton.