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

年龄相关性骨质疏松症中的糖皮质激素、骨细胞和骨强度

• 批准号: 8073008
• 负责人: ROBERT Stewart WEINSTEIN
• 金额: $ 27.1万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073008
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Ablation; Adrenal Glands; Adverse effects; Affect; Age; Age-Months; Age-Related Bone Loss; Aging; Americas; Amplifiers; Anoikis; Apoptosis; Biomechanics; Blood Circulation; Bone Density; Bone Resorption; C57BL/6 Mouse; Caspase; Cells; Cessation of life; Detection; Deterioration; Diphtheria Toxin; Enzymes; Exhibits; Extracellular Matrix; Focal Adhesion Kinase 1; Focal Adhesions; Fracture; Glucocorticoid Receptor; Glucocorticoids; Human; Hydrocortisone; Hydroxysteroid Dehydrogenases; In Vitro; Investigation; KRP protein; Longevity; Mediating; Modeling; Mus; Nutrient; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Prevalence; Prevention; Production; Property; Proteins; Research Personnel; Risk; Role; Signal Transduction; Skeleton; Spinal; Study Section; Testing; Tissues; Transgenic Animals; Transgenic Mice; Work; age related; base; bisphosphonate; bone; bone cell; bone loss; bone mass; bone quality; bone strength; dentin matrix protein 1; diphtheria toxin receptor; falls; in vivo; innovation; mature animal; overexpression; promoter; protein tyrosine kinase PYK2; receptor; repaired; skeletal; spine bone structure; stress-activated protein kinase 1; tartrate-resistant acid phosphatase; wasting

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.

基于糖皮质激素引起的骨强度损失的发现，部分原因是由于