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

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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.