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PGC1β Mediates PPARγ Activation of Osteoclastogenesis and Rosiglitazone-Induced Bone Loss

Long-term usage of rosiglitazone, a synthetic PPARγ agonist, increases fracture rates among diabetic patients. PPARγ suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse m...

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Bibliographic Details
Published in:Cell metabolism 2010-06, Vol.11 (6), p.503-516
Main Authors: Wei, Wei, Wang, Xueqian, Yang, Marie, Smith, Leslie C., Dechow, Paul C., Wan, Yihong
Format: Article
Language:English
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Summary:Long-term usage of rosiglitazone, a synthetic PPARγ agonist, increases fracture rates among diabetic patients. PPARγ suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPARγ, PGC1β, or ERRα, here we show that PGC1β is required for the resorption-enhancing effects of rosiglitazone. PPARγ activation indirectly induces PGC1β expression by downregulating β-catenin and derepressing c-jun. PGC1β, in turn, functions as a PPARγ coactivator to stimulate osteoclast differentiation. Complementarily, PPARγ also induces ERRα expression, which coordinates with PGC1β to enhance mitochondrial biogenesis and osteoclast function. ERRα knockout mice exhibit osteoclast defects, revealing ERRα as an important regulator of osteoclastogenesis. Strikingly, PGC1β deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1β as an essential mediator for the PPARγ stimulation of osteoclastogenesis by targeting both PPARγ itself and ERRα, thus activating two distinct transcriptional programs. [Display omitted] ► PPARγ activation induces PGC1β during osteoclast differentiation ► PGC1β acts as a PPARγ coactivator to stimulate osteoclast differentiation ► PGC1β coordinates with ERRα to enhance osteoclast function ► Osteoclastic PGC1β is required for rosiglitazone-induced bone loss in vivo
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2010.04.015