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Published on: March 28, 2013

PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss

Wei Wei1, Xueqian Wang, Marie Yang

  • 1Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Cell Metabolism
|June 4, 2010
PubMed

Insights

Rosiglitazone increases fracture risk by promoting bone breakdown. PGC1beta is essential for this effect, mediating rosiglitazone

Area of Science:

  • Molecular Endocrinology
  • Bone Biology
  • Metabolic Disease Research

Background:

  • Long-term rosiglitazone use is linked to increased fracture rates in diabetic patients.
  • PPARgamma activation by rosiglitazone suppresses bone formation and enhances bone resorption.
  • The precise molecular mechanisms underlying rosiglitazone-induced bone loss require elucidation.

Purpose of the Study:

  • To investigate the role of PGC1beta and ERRalpha in mediating the bone-resorbing effects of rosiglitazone.
  • To identify the molecular pathways through which PPARgamma activation leads to decreased bone mass.

Main Methods:

  • Utilized mouse models with genetic alterations in PPARgamma, PGC1beta, and ERRalpha.
  • Examined the impact of rosiglitazone on osteoblastogenesis and osteoclastogenesis.
  • Assessed the effects of PGC1beta and ERRalpha deletion on rosiglitazone-induced bone loss.

Main Results:

  • PGC1beta is indispensable for rosiglitazone's bone resorption-enhancing effects.
  • PPARgamma activation upregulates PGC1beta expression, which coactivates PPARgamma to promote osteoclast differentiation.
  • PPARgamma also induces ERRalpha, which works with PGC1beta to boost mitochondrial biogenesis and osteoclast function.
  • ERRalpha knockout mice display osteoclast defects, highlighting ERRalpha's role in osteoclastogenesis.
  • Deletion of PGC1beta in osteoclasts completely prevents rosiglitazone-induced bone loss.

Conclusions:

  • PGC1beta is a critical mediator of PPARgamma-stimulated osteoclastogenesis and rosiglitazone-induced bone loss.
  • Rosiglitazone triggers two distinct transcriptional programs via PGC1beta and ERRalpha, leading to enhanced bone resorption.
  • Targeting the PGC1beta-ERRalpha axis may offer therapeutic strategies for mitigating bone loss associated with PPARgamma agonists.

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