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

Long-term usage of rosiglitazone, a synthetic PPAR gamma agonist, increases fracture rates among diabetic patients. PPAR gamma suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPAR gamma, PGC1 beta, or ERR alpha, here we show that PGC1 beta is required for the resorption-enhancing effects of rosiglitazone. PPAR gamma activation indirectly induces PGC1 beta expression by downregulating beta-catenin and derepressing c-jun. PGC1 beta, in turn, functions as a PPAR gamma coactivator to stimulate osteoclast differentiation. Complementarily, PPAR gamma also induces ERR alpha expression, which coordinates with PGC1 beta to enhance mitochondrial biogenesis and osteoclast function. ERR alpha knockout mice exhibit osteoclast defects, revealing ERR alpha as an important regulator of osteoclastogenesis. Strikingly, PGC1 beta deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1 beta as an essential mediator for the PPAR gamma stimulation of osteoclastogenesis by targeting both PPAR gamma itself and ERR alpha, thus activating two distinct transcriptional programs.