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J. Biol. Chem., Vol. 278, Issue 50, 50259-50272, December 12, 2003

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Proteasomal Degradation of Runx2 Shortens Parathyroid Hormone-induced Anti-apoptotic Signaling in Osteoblasts

A PUTATIVE EXPLANATION FOR WHY INTERMITTENT ADMINISTRATION IS NEEDED FOR BONE ANABOLISM^*

Teresita Bellido, A. Afshan Ali, Lilian I. Plotkin, Qiang Fu, Igor Gubrij, Paula K. Roberson, Robert S. Weinstein, Charles A. O'Brien, Stavros C. Manolagas, and Robert L. Jilka

From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205

It is unknown why sustained elevation of parathyroid hormone (PTH) stimulates bone resorption, whereas intermittent administration stimulates bone formation. We show in mice that daily injections of PTH attenuate osteoblast apoptosis, thereby increasing osteoblast number, bone formation rate, and bone mass, but do not affect osteoclast number. In contrast, sustained elevation of PTH, achieved either by infusion or by raising endogenous hormone secretion with a calcium-deficient diet, does not affect osteoblast apoptosis but increases osteoclast number. Attenuation of apoptosis by PTH in cultured osteoblastic cells requires protein kinase A-mediated phosphorylation and inactivation of the pro-apoptotic protein Bad as well as transcription of survival genes, like Bcl-2, mediated by CREB (cAMP response element-binding protein) and Runx2. But, PTH also increases proteasomal proteolysis of Runx2. Moreover, the anti-apoptotic effect of PTH is prolonged by inhibition of proteasomal activity, by overexpressing a dominant negative form of the E3 ligase (ubiquitin-protein isopeptide ligase) that targets Runx2 for degradation (Smurf1), or by overexpressing Runx2 itself. The duration of the anti-apoptotic effect of PTH, thus, depends on the level of Runx2, which in turn is decreased by PTH via Smurf1-mediated proteasomal proteolysis. The self-limiting nature of PTH-induced survival signaling might explain why intermittent administration of the hormone is required for bone anabolism.

Received for publication, July 11, 2003 , and in revised form, September 5, 2003.

^* This work was supported by the Department of Veterans Affairs and by National Institutes of Health Grants R01 AR46823 (to R. L. J.) and K02 AR02127 (to T. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental methods, references, and Figs. 1–5.

To whom correspondence should be addressed: Division of Endocrinology and Metabolism, Slot 587, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205. Tel.: 501-686-7896; Fax: 501-686-8954; E-mail: RLJilka{at}uams.edu.

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