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

SUMMARY Long-term usage of rosiglitazone, a synthetic PPARg agonist, increases fracture rates among diabetic patients. PPARg suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPARg, PGC1b ,o r ERRa, here we show that PGC1b is required for the resorption-enhancing effects of rosiglitazone. PPARg activation indirectly induces PGC1b expression by downregulating b-catenin and derepressing c-jun. PGC1b, in turn, functions as a PPARg coactivator to stimulate osteoclast differentiation. Complementarily, PPARg also induces ERRa expression, which coordinates with PGC1b to enhance mitochondrial biogenesis and osteoclast function. ERRa knockout mice exhibit osteoclast defects, revealing ERRa as an important regulator of osteoclastogenesis. Strikingly, PGC1b deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1b as an essential mediator for the PPARg stimulation of osteoclastogenesis by targeting both PPARg itself and ERRa, thus activating two distinct transcriptional programs.