title: PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption.
abstract: 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.
authors.affiliation: Dept. Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States; Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, OH 43614, United States.
authors.forename: L A
authors.initials: LA
authors.lastname: Stechschulte
authors.affiliation: Dept. Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States.
authors.forename: P J
authors.initials: PJ
authors.lastname: Czernik
authors.affiliation: Dept. Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States.
authors.forename: Z C
authors.initials: ZC
authors.lastname: Rotter
authors.affiliation: Dept. Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States.
authors.forename: F N
authors.initials: FN
authors.lastname: Tausif
authors.affiliation: Dept. Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States.
authors.forename: C A
authors.initials: CA
authors.lastname: Corzo
authors.affiliation: Dept. Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States.
authors.forename: D P
authors.initials: DP
authors.lastname: Marciano
authors.affiliation: Dept. Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States.
authors.forename: A
authors.initials: A
authors.lastname: Asteian
authors.affiliation: Dept. Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States.
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.affiliation: School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
authors.forename: J B
authors.initials: JB
authors.lastname: Bruning
authors.affiliation: Dept. Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States.
authors.forename: T M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Maine Medical Center Research Institute, Scarborough, ME 04074, United States.
authors.forename: C J
authors.initials: CJ
authors.lastname: Rosen
authors.affiliation: Dept. Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, United States. Electronic address: pgriffin@scripps.edu.
authors.forename: P R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Dept. Orthopaedic Surgery, University of Toledo Health Science Campus, Toledo, OH 43614, United States; Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, OH 43614, United States; Dept. Physiology and Pharmacology, University of Toledo Health Science Campus, Toledo, OH 43614, United States. Electronic address: beata.leckaczernik@utoledo.edu.
authors.forename: B
authors.initials: B
authors.lastname: Lecka-Czernik
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D023421:Models, Animal; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010011:Osteocytes / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D055114:X-Ray Microtomography
chemical_list: D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: Adipocyte; Bone; Insulin sensitizers; Osteoblast; Osteoclast; Osteocyte; PPARγ; Post-translational modifications