TY - JOUR
T1 - PGC1β mediates PPARγ activation of osteoclastogenesis and rosiglitazone-induced bone loss
AU - Wei, Wei
AU - Wang, Xueqian
AU - Yang, Marie
AU - Smith, Leslie C.
AU - Dechow, Paul C.
AU - Wan, Yihong
N1 - Funding Information:
We would like to thank R. Evans (Salk Institute) for providing the PGC1β flox/flox mice; V. Giguère (McGill University) for providing the ERRα KO mice; D. Mangelsdorf, S. Kliewer, J. Zerwekh, O. Oz (University of Texas Southwestern Medical Center), and J. Sonoda (Salk Institute) for helpful discussion; and A. Gray for administrative assistance. Y.W. is a Virginia Murchison Linthicum Scholar in Medical Research. This work was supported by the University of Texas Southwestern Medical Center Endowed Scholar Startup Fund, a BD Biosciences Research Grant Award, and CPRIT funding (RP100841).
PY - 2010/6/9
Y1 - 2010/6/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2010.04.015
DO - 10.1016/j.cmet.2010.04.015
M3 - Article
C2 - 20519122
AN - SCOPUS:77956408841
SN - 1550-4131
VL - 11
SP - 503
EP - 516
JO - Cell Metabolism
JF - Cell Metabolism
IS - 6
ER -