A Short-Lived Antiapoptotic Effect

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Science's STKE  16 Dec 2003:
Vol. 2003, Issue 213, pp. tw489
DOI: 10.1126/stke.2132003tw489

Osteoporosis, a degenerative disease defined by increasing bone fragility, is associated with substantial morbidity and mortality. Although several treatments can inhibit bone resorption by osteoclasts, intermittent administration of parathyroid hormone (PTH) stimulates formation of new bone. Continuous elevation of PTH, however, as found in hyperparathyroidism, results in bone loss. To investigate the mechanisms underlying these paradoxical effects, Bellido et al. compared the effects on bone metabolism in mice of intermittent treatment with PTH to those of sustained PTH elevation. In mice receiving intermittent PTH, increased bone mineral density correlated with a reduction in osteoblast apoptosis, along with an increase in osteoblast number. Sustained PTH elevation had no effect on osteoblast apoptosis and elicited a more modest increase in osteoblast number, as well as an increase in osteoclast number. PTH suppression of apoptosis in cultured osteoblastic cells was short-lived (lasting less than 24 hours) and depended on protein kinase A-mediated phosphorylation of Bad and on the presence of Bcl-2, cyclic AMP response element-binding protein, and the osteoblast-specific transcription factor runt-related transcription factor 2 (Runx2). Runx2 was required for a PTH-dependent increase in Bcl-2 mRNA and protein. Pharmacologic analysis, combined with transfectional analysis involving various dominant-negative mutants and a Runx2 mutant that cannot be targeted for degradation, and Runx2 overexpression, indicated that PTH-stimulated proteasomal degradation of Runx2 limited the duration of PTH's antiapoptotic effect. The requirement for Runx-2 in PTH's antiapoptotic effect, combined with PTH-dependent Runx2 degradation, may explain the inability of sustained exposure to PTH to suppress osteoblast apoptosis and to promote the formation of new bone.

T. Bellido, A. A. Ali, L. I. Plotkin, Q. Fu, I. Gubrij, P. K. Roberson, R. S. Weinstein, C. A. O'Brien, S. C. Manolagas, R. L. Jilka, Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts. J. Biol. Chem. 278, 50259-50272 (2003). [Abstract] [Full Text]

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