PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss.
Long-term usage of rosiglitazone, a synthetic PPARgamma agonist, increases fracture rates among diabetic patients. PPARgamma suppresses osteoblastogenesis while activating osteoclastogenesis, suggesting that rosiglitazone decreases bone formation while sustaining or increasing bone resorption. Using mouse models with genetically altered PPARgamma, PGC1beta, or ERRalpha, here we show that PGC1beta is required for the resorption-enhancing effects of rosiglitazone. PPARgamma activation indirectly induces PGC1beta expression by downregulating beta-catenin and derepressing c-jun. PGC1beta, in turn, functions as a PPARgamma coactivator to stimulate osteoclast differentiation. Complementarily, PPARgamma also induces ERRalpha expression, which coordinates with PGC1beta to enhance mitochondrial biogenesis and osteoclast function. ERRalpha knockout mice exhibit osteoclast defects, revealing ERRalpha as an important regulator of osteoclastogenesis. Strikingly, PGC1beta deletion in osteoclasts confers complete resistance to rosiglitazone-induced bone loss. These findings identify PGC1beta as an essential mediator for the PPARgamma stimulation of osteoclastogenesis by targeting both PPARgamma itself and ERRalpha, thus activating two distinct transcriptional programs.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Wei
W
Wei
Xueqian
X
Wang
Marie
M
Yang
Leslie C
LC
Smith
Paul C
PC
Dechow
Junichiro
J
Sonoda
Ronald M
RM
Evans
Yihong
Y
Wan
D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced*; D002454:Cell Differentiation; D002460:Cell Line; D006801:Humans; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000633:toxicity*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D051176:beta Catenin / Q000378:metabolism; D000097983:ERRalpha Estrogen-Related Receptor
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016755:Proto-Oncogene Proteins c-jun; D011960:Receptors, Estrogen; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse