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Endocrinology Vol. 143, No. 6 2376-2384
Copyright © 2002 by The Endocrine Society

RECEPTORS

Divergent Effects of Selective Peroxisome Proliferator-Activated Receptor-{gamma}2 Ligands on Adipocyte Versus Osteoblast Differentiation

Beata Lecka-Czernik, Elena J. Moerman, David F. Grant, Jürgen M. Lehmann, Stavros C. Manolagas and Robert L. Jilka

Department of Geriatrics, Reynolds Center on Aging (B.L.-C., E.J.M.), Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases (B.L.-C., S.C.M., R.L.J.), Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; Department of Pharmaceutical Sciences, University of Connecticut (D.F.G.), Storrs, Connecticut 06269-2092; and Tularik, Inc. (J.M.L.), South San Francisco, California 94080

Address all correspondence and requests for reprints to: Dr. Beata Lecka-Czernik, Department of Geriatrics, Reynolds Center on Aging, University of Arkansas for Medical Sciences, Slot 807, 629 South Elm Street, Little Rock, Arkansas 72205. E-mail: . leckaczernikbeata{at}uams.edu

PPAR{gamma} is activated by diverse ligands and regulates the differentiation of many cell types. Based on evidence that activation of PPAR{gamma}2 by rosiglitazone stimulates adipogenesis and inhibits osteoblastogenesis in U-33/{gamma}2 cells, a model mesenchymal progenitor of adipocytes and osteoblasts, we postulated that the increase in marrow fat and the decrease in osteoblast number that occur during aging are due to increased PPAR{gamma}2 activation. Here, we show that the naturally occurring PPAR{gamma} ligands 9,10-dihydroxyoctadecenoic acid, and 15-deoxy-{Delta}12,14-PGJ2, also stimulate adipocytes and inhibit osteoblast differentiation of U-33/{gamma}2 cells. Strikingly, 9,10-epoxyoctadecenoic acid and the thiazolidine acetamide ligand GW0072 [(±)-(2S,5S)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thaizolidineN,N-dibenzyl-acetamide] prevent osteoblast differentiation, but do not stimulate adipogenesis, whereas 9-hydroxyoctadecadienoic acid stimulates adipogenesis but does not affect osteoblast differentiation. The divergent effects of PPAR{gamma}2 ligands on osteoblast and adipocyte differentiation were confirmed in primary murine bone marrow cultures using rosiglitazone and GW0072. These findings indicate that the proadipogenic and antiosteoblastogenic effects of PPAR{gamma}2 are mediated by distinct regulatory pathways that can be differentially modulated depending on the nature of the ligand, and they support the idea that increased fatty acid oxidation during aging may inhibit osteoblast differentiation. Moreover, there may be selective PPAR{gamma}2 modulators that block the adverse effects of fatty acid oxidation products while retaining beneficial activities such as insulin sensitization.




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