title: Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids.
abstract: Glucocorticoids depress bone formation by inhibiting osteoblastogenesis and increasing osteoblast apoptosis. However, the role of bone resorption in the initial rapid phase of bone loss characteristic of glucocorticoid-induced osteoporosis is unexplained, and the reason for the efficacy of bisphosphonates in this condition remains unknown. We report that in murine osteoclast cultures, glucocorticoids prolonged the baseline survival of osteoclasts and antagonized bisphosphonate-induced caspase activation and apoptosis by a glucocorticoid receptor-mediated action. Consistent with the in vitro evidence, in a murine model of glucocorticoid-induced osteoporosis, the number of cancellous osteoclasts increased, even though osteoclast progenitor number was reduced. Moreover, in mice receiving both glucocorticoids and bisphosphonates, the expected proapoptotic effect of bisphosphonates on osteoclasts was abrogated, as evidenced by maintenance of osteoclast numbers and, additionally, loss of bone density. In contrast, bisphosphonate administration prevented glucocorticoid-induced osteoblast apoptosis. These results indicate that the early loss of bone with glucocorticoid excess is caused by extension of the life span of pre-existing osteoclasts, an effect not preventable by bisphosphonates. Therefore, the early beneficial effects of these agents must be due, in part, to prolonging the life span of osteoblasts.
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205-7199, USA. weinsteinroberts@uams.edu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.forename: Jin-Ran
authors.initials: JR
authors.lastname: Chen
authors.forename: Cara C
authors.initials: CC
authors.lastname: Powers
authors.forename: Scott A
authors.initials: SA
authors.lastname: Stewart
authors.forename: Reid D
authors.initials: RD
authors.lastname: Landes
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.forename: A Michael
authors.initials: AM
authors.lastname: Parfitt
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D010024:Osteoporosis / Q000139:chemically induced / Q000473:pathology; D011239:Prednisolone / Q000494:pharmacology
chemical_list: D005938:Glucocorticoids; D003907:Dexamethasone; D011239:Prednisolone; D019386:Alendronate