Pharmacological repression of PPARĪ³ promotes osteogenesis
Date
2015
Authors
Marciano, D.
Kuruvilla, D.
Boregowda, S.
Asteian, A.
Hughes, T.
Garcia-Ordonez, R.
Corzo, C.
Khan, T.
Novick, S.
Park, H.
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Journal article
Citation
Nature Communications, 2015; 6(1):7443-1-7443-7
Statement of Responsibility
David P. Marciano, Dana S. Kuruvilla, Siddaraju V. Boregowda, Alice Asteian, Travis S. Hughes, Ruben Garcia-Ordonez, Cesar A. Corzo, Tanya M. Khan, Scott J. Novick, HaJeung Park, Douglas J. Kojetin, Donald G. Phinney, John B. Bruning, Theodore M. Kamenecka, Patrick R. Griffin
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Abstract
The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARĪ³) is the master regulator of adipogenesis and the pharmacological target of the thiazolidinedione (TZD) class of insulin sensitizers. Activation of PPARĪ³ by TZDs promotes adipogenesis at the expense of osteoblast formation, contributing to their associated adverse effects on bone. Recently, we reported the development of PPARĪ³ 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 PPARĪ³, 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 PPARĪ³ repression, and suggest a therapeutic approach to promote bone formation.
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