PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption

• PPARγ S273 regulates osteoclast differentiation and insulin sensitivity
• PPARγ S112 regulates osteoblast and adipocyte differentiation
• PPARγ and PPARα regulate osteocyte activities of bone formation and turnover
• SR10171, a PPARγ inverse agonist and PPARα weak agonist, is anabolic for boneDiabetes is a condition with compromised energy balance and is associated with bone fractures. Some treatment options for diabetes sensitize the patient to insulin via targeting the transcription factor PPARγ. PPARγ is also key regulator of bone formation and bone resorption. Anti-diabetic drugs TZDs target PPARγ protein and this leads to bone loss and increase in fractures in postmenopausal women. Bone mass and energy metabolism share similar regulating pathways, and here we demonstrate a new class of insulin sensitizers that is a selective modulator of PPARγ activity; resulting in a pharmacologic agent that can be beneficial for both diabetes and metabolic bone disease.

The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities. Treatment of either hyperglycemic or normoglycemic animals with SR10171, an inverse agonist that blocks pS273 but not pS112, increased trabecular and cortical bone while normalizing metabolic parameters. Additionally, SR10171 treatment modulated osteocyte, osteoblast, and osteoclast activities, and decreased marrow adiposity. These data demonstrate that regulation of bone mass and energy metabolism shares similar mechanisms suggesting that one pharmacologic agent could be developed to treat both diabetes and metabolic bone disease.

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