The Role of Osteocyte Survival in Bone Strength

描述(申请人提供)：糖皮质激素引起的骨质疏松症是这种疾病最常见的继发性形式，接受长期治疗的患者中高达50%将遭受骨质疏松性骨折。在使用糖皮质激素的第一年中，骨密度(BMD)下降了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了75%，这表明糖皮质激素过量对骨骼的不利影响是由于似乎与骨密度下降分开的异常。事实上，很明显，骨密度只是影响骨骼强度的几个因素之一。骨骼大小、建筑和材料特性分别起到了作用。在这一应用中，有人认为糖皮质激素过量对骨骼的不利影响部分是由于骨细胞凋亡发生率的增加，以及骨细胞凋亡通过降低骨材料特性、允许受损骨积累或两者兼而有之而对骨强度产生负面影响。为了推进这一假说，有人建议：(1)利用骨钙素启动子，通过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)来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受体到达之前灭活糖皮质激素的酶，从而保护这些细胞免受糖皮质激素诱导的凋亡。(2)在抗酒石酸酸性磷酸酶启动子的控制下过表达11b-HSD2，以保护转基因小鼠的破骨细胞免受糖皮质激素的影响，从而防止糖皮质激素诱导的早期骨丢失，从而创造了确定骨细胞凋亡和骨强度损失是否仍会发生的机会；(3)在骨钙素启动子的控制下，利用表达白喉毒素受体的转基因小鼠快速消融骨细胞和成熟成骨细胞，以确定在骨密度和骨微结构改变之前是否降低了骨强度。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.