Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids

Robert S. Weinstein, Jin Ran Chen, Cara C. Powers, Scott A. Stewart, Reid D. Landes, Teresita Bellido, Robert L. Jilka, A. Michael Parfitt, Stavros C. Manolagas

Research output: Contribution to journalArticle

294 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1041-1048
Number of pages8
JournalJournal of Clinical Investigation
Volume109
Issue number8
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Medicine(all)

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