PGC1β mediates PPARγ activation of osteoclastogenesis and rosiglitazone-induced bone loss

Wei Wei, Xueqian Wang, Marie Yang, Leslie C. Smith, Paul C. Dechow, Yihong Wan

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)503-516
Number of pages14
JournalCell Metabolism
Volume11
Issue number6
DOIs
StatePublished - Jun 9 2010

Fingerprint

rosiglitazone
Peroxisome Proliferator-Activated Receptors
Osteogenesis
Bone and Bones
Osteoclasts
Catenins
Organelle Biogenesis
Bone Resorption
Knockout Mice

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

PGC1β mediates PPARγ activation of osteoclastogenesis and rosiglitazone-induced bone loss. / Wei, Wei; Wang, Xueqian; Yang, Marie; Smith, Leslie C.; Dechow, Paul C.; Wan, Yihong.

In: Cell Metabolism, Vol. 11, No. 6, 09.06.2010, p. 503-516.

Research output: Contribution to journalArticle

Wei, Wei ; Wang, Xueqian ; Yang, Marie ; Smith, Leslie C. ; Dechow, Paul C. ; Wan, Yihong. / PGC1β mediates PPARγ activation of osteoclastogenesis and rosiglitazone-induced bone loss. In: Cell Metabolism. 2010 ; Vol. 11, No. 6. pp. 503-516.
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