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. ? ?
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