This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnson, T. E. Articles by Schmidt, A. Search for Related Content PubMed PubMed Citation Articles by Johnson, T. E. Articles by Schmidt, A.

Thiazolidinedione Effects on Glucocorticoid Receptor-Mediated Gene Transcription and Differentiation in Osteoblastic Cells

Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, Pennsylvania 19486

Address all correspondence and requests for reprints to: Azriel Schmidt, Ph.D., Merck Research Laboratories, WP 26A-1000, West Point, Pennsylvania 19486.

The glucocorticoid receptor (GR) and peroxisome proliferator-activated receptors (PPARs) play important roles in the differentiation of mesenchymal cells. Glucocorticoids acting via the GR promote osteoblastic differentiation of bone marrow stromal cells, whereas PPAR ligands induce these cells to become adipocytes. To explore potential interactions between PPAR and GR pathways in osteoblasts, we studied the interaction between PPAR subtype-selective ligands and dexamethasone (DEX) in a murine calvaria-derived osteoblastic cell line (MB 1.8) that expresses endogenous GR and PPARs. In ligand-dependent transcription assays, the PPAR-selective ligand TZD [(5-(4-N-methyl-N(2-pyridyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione], a thiazolidinedione antidiabetic, enhanced the effect of DEX to stimulate transcription of a glucocorticoid-inducible reporter gene (mouse mammary tumor virus-luciferase). No effect was seen with PPAR- or hNUC1/PPAR-selective ligands. The GR antagonist RU-486 inhibited the DEX and TZD responses, suggesting that the effects were mediated through endogenous GR. TZD also enhanced glucocorticoid-mediated transcription in SaOS-2/B10 human osteosarcomatous cells, but not in CV-1 cells, even though both cell lines were transfected with GR plasmid and expressed significant levels of endogenous PPAR messenger RNA. In MB 1.8 cells, TZD decreased alkaline phosphatase activity and the expression of osteoblast-associated genes while it up-regulated the adipocyte fatty acid-binding protein. DEX counteracted the effects of TZD on alkaline phosphatase enzyme activity and osteoblastic gene expression, but enhanced the actions of TZD on adipocyte fatty acid-binding protein. Interestingly, TZD inhibited in vitro bone nodule formation and mineralization, and DEX counteracted this effect. Thus, depending on the promoter context, TZD and DEX can oppose or enhance each other’s actions on gene transcription. Collectively, these results point to a complex interaction between PPAR and GR signaling pathways that regulates the effects of TZD and DEX on osteoblastic differentiation. The mechanism of this interaction is still under investigation, but might involve PPAR-dependent and -independent pathways. As thiazolidinediones represent an important new class of drugs, our findings also raise the need for further studies in bone.

This article has been cited by other articles:

				I. Takada and S. Kato A New PPAR-{gamma} Function in Bone IBMS BoneKEy, July 1, 2008; 5(7): 258 - 261. [Full Text] [PDF]

				M. Nie, L. Corbett, A. J. Knox, and L. Pang Differential Regulation of Chemokine Expression by Peroxisome Proliferator-activated Receptor {gamma} Agonists: INTERACTIONS WITH GLUCOCORTICOIDS AND {beta}2-AGONISTS J. Biol. Chem., January 28, 2005; 280(4): 2550 - 2561. [Abstract] [Full Text] [PDF]

				J. P. Girod and D. J. Brotman Does altered glucocorticoid homeostasis increase cardiovascular risk? Cardiovasc Res, November 1, 2004; 64(2): 217 - 226. [Abstract] [Full Text] [PDF]

				M T Rae, D Niven, A Ross, T Forster, R Lathe, H O D Critchley, P Ghazal, and S G Hillier Steroid signalling in human ovarian surface epithelial cells: the response to interleukin-1{alpha} determined by microarray analysis J. Endocrinol., October 1, 2004; 183(1): 19 - 28. [Abstract] [Full Text] [PDF]

				S. M. Willi, A. Kennedy, P. Wallace, E. Ganaway, N. L. Rogers, and W. T. Garvey Troglitazone Antagonizes Metabolic Effects of Glucocorticoids in Humans: Effects on Glucose Tolerance, Insulin Sensitivity, Suppression of Free Fatty Acids, and Leptin Diabetes, October 1, 2002; 51(10): 2895 - 2902. [Abstract] [Full Text] [PDF]

				P. D. Schoppee, J. C. Garmey, and J. D. Veldhuis Putative Activation of the Peroxisome Proliferator-Activated Receptor {gamma} Impairs Androgen and Enhances Progesterone Biosynthesis in Primary Cultures of Porcine Theca Cells Biol Reprod, January 1, 2002; 66(1): 190 - 198. [Abstract] [Full Text]