The Role of Osteocyte Survival in Bone Strength

描述（由申请人提供）：糖皮质激素诱导的骨质疏松症是该疾病最常见的继发性形式，高达50%的接受长期治疗的患者将发生骨质疏松性骨折。在糖皮质激素给药的第一年，骨矿物质密度（BMD）降低6 - 12%，但骨折的相对风险增加得更快，在治疗的前三个月内上升高达75%，这表明糖皮质激素过量对骨的不良影响是由于似乎与BMD下降无关的异常。事实上，很明显，BMD只是影响骨强度的几个因素之一。骨大小、结构和材料特性分别起作用。在本申请中，提出糖皮质激素过量对骨骼的不良影响的一部分是由于骨细胞凋亡的发生率增加，并且骨细胞凋亡通过降解骨材料性质、通过允许受损骨的积累或两者来对骨强度产生负面影响。为了推进这一假设，我们提出：（1）通过使用骨钙素启动子在转基因小鼠的成骨细胞和骨细胞中过表达11b-羟基类固醇脱氢酶2（11b-HSD2），从而保护这些细胞免受糖皮质激素诱导的凋亡，从而确定糖皮质激素诱导的骨细胞凋亡对骨强度的贡献，11b-HSD2是一种在糖皮质激素到达糖皮质激素受体之前使糖皮质激素失活的酶。（2）在抗酒石酸酸性磷酸酶启动子的控制下过表达11b-HSD2，以保护转基因小鼠中的破骨细胞免受糖皮质激素暴露，从而防止糖皮质激素诱导的早期骨丢失，并创造机会确定骨细胞凋亡和骨强度损失是否仍然发生;（3）通过使用在骨钙蛋白启动子控制下表达白喉毒素受体的转基因小鼠，用白喉毒素快速消融骨细胞和成熟成骨细胞，以确定骨强度是否在BMD和微结构改变之前降低。拟议的研究计划将揭示骨细胞存活在骨强度中的作用以及骨细胞如何实现这一目标。

DESCRIPTION (provided by applicant): Glucocorticoid-induced osteoporosis is the most common secondary form of the disorder and up to 50% of patients receiving long-term therapy will suffer an osteoporotic fracture. Bone mineral density (BMD) decreases by 6-12% during the first year of administration of glucocorticoids but the relative risk of fracture increases more rapidly, escalating by as much as 75% within the first three months of treatment, suggesting that the adverse effects of glucocorticoid excess on bone are due to abnormalities seemingly separate from the decline in BMD. Indeed, it is clear that BMD is only one of several factors contributing to bone strength. Bone size, architecture and material properties make separate contributions. In this application, it is proposed that part of the adverse skeletal impact of glucocorticoid excess is due to an increase in the prevalence of osteocyte apoptosis and that osteocyte apoptosis negatively affects bone strength by degrading bone material properties, by allowing accumulation of damaged bone, or both. To advance this hypothesis, it is proposed to: (1) Establish the contributions of glucocorticoid-induced osteocyte apoptosis to bone strength by overexpressing 11b-hydroxysteroid dehydrogenase 2 (11b-HSD2), an enzyme that inactivates glucocorticoids before they reach the glucocorticoid receptor, in osteoblasts and osteocytes of transgenic mice by using the osteocalcin promoter and thereby protecting these cells from glucocorticoid-induced apoptosis. Determine how strength is maintained in spite of loss of BMD or changes in cancellous and cortical microarchitecture; (2) Overexpress 11b-HSD2 under control of the tartrate-resistant acid phosphatase promoter to guard osteoclasts in transgenic mice from glucocorticoid exposure thus preventing the glucocorticoid-induced early loss of bone and creating the opportunity to determine if osteocyte apoptosis and loss of bone strength occur nonetheless; (3) Rapidly ablate osteocytes and mature osteoblasts with diphtheria toxin by using transgenic mice expressing the diphtheria toxin receptor under control of the osteocalcin promoter to determine if bone strength is decreased before BMD and microarchitecture are altered. The proposed research plan will reveal the role of osteocyte survival in bone strength and how osteocytes achieve this objective.