title: Pharmacological repression of PPARγ promotes osteogenesis.
abstract: The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulator of adipogenesis and the pharmacological target of the thiazolidinedione (TZD) class of insulin sensitizers. Activation of PPARγ by TZDs promotes adipogenesis at the expense of osteoblast formation, contributing to their associated adverse effects on bone. Recently, we reported the development of PPARγ antagonist SR1664, designed to block the obesity-induced phosphorylation of serine 273 (S273) in the absence of classical agonism, to derive insulin-sensitizing efficacy with improved therapeutic index. Here we identify the structural mechanism by which SR1664 actively antagonizes PPARγ, and extend these findings to develop the inverse agonist SR2595. Treatment of isolated bone marrow-derived mesenchymal stem cells with SR2595 promotes induction of osteogenic differentiation. Together these results identify the structural determinants of ligand-mediated PPARγ repression, and suggest a therapeutic approach to promote bone formation.
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Marciano
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Kuruvilla
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Siddaraju V
authors.initials: SV
authors.lastname: Boregowda
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Asteian
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Travis S
authors.initials: TS
authors.lastname: Hughes
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Garcia-Ordonez
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Corzo
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Khan
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Novick
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Phinney
authors.affiliation: School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Bruning
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Departments of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter FL33458, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D003461:Crystallography; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects
chemical_list: C561901:(S)-4'-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid; D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D007211:Indoles; D047495:PPAR gamma; C000606395:SR2595