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

被引:302
作者
Bellido, T [1 ]
Ali, AA [1 ]
Plotkin, LI [1 ]
Fu, Q [1 ]
Gubrij, I [1 ]
Roberson, PK [1 ]
Weinstein, RS [1 ]
O'Brien, CA [1 ]
Manolagas, SC [1 ]
Jilka, RL [1 ]
机构
[1] Univ Arkansas Med Sci, Div Endocrinol & Metab, Ctr Osteoporosis & Metab Bone Dis, Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA
关键词
D O I
10.1074/jbc.M307444200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:50259 / 50272
页数:14
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