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J. Biol. Chem., Vol. 280, Issue 24, 22688-22696, June 17, 2005

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Hypoxia Inhibition of Adipocytogenesis in Human Bone Marrow Stromal Cells Requires Transforming Growth Factor-/Smad3 Signaling^*

Shuanhu Zhou, Stanislav Lechpammer, Joel S. Greenberger, and Julie Glowacki¶

From the Department of Orthopedic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 and the Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213

Although hypoxia and transforming growth factor- (TGF-) inhibit differentiation of adipocytes from preadipocytes and bone marrow-derived cells in several species, the relationship between hypoxia and TGF- signaling in adipocytogenesis is unknown. In this study, we evaluated the mechanisms of inhibition of adipocyte differentiation by hypoxia and TGF- in human and murine marrow stromal cells (MSCs) and the role of TGF-/Smad signaling in the inhibition of adipocytogenesis by hypoxia. Both hypoxia-mimetic deferoxamine mesylate (DFO) and TGF-1 inhibited adipocyte differentiation (1.0% versus the control at 15 µM DFO and 1.4% versus the control at 1 ng/ml TGF-1) and adipocyte gene expression (peroxisome proliferator-activated receptor-2 and lipoprotein lipase) in human MSCs after 21 days of treatment. Hypoxia (2% O₂) and DFO (but not TGF-1) increased hypoxia-inducible factor-1 as shown by Western blotting. Macroarrays and Western and Northern blot analyses showed that hypoxia activated the TGF-/Smad signaling pathway and that both hypoxia and TGF-1 modulated adipocyte differentiation pathways such as the insulin-, peroxisome proliferator-activated receptor--, phosphatidylinositol 3-kinase-, and MAPK-associated signaling pathways. Studies with mouse marrow stromal cell lines derived from Smad3^+/+ or Smad3^–/– mice revealed that the TGF- type I receptor (ALK-5) and its intracellular signaling molecule Smad3 were necessary for the inhibition of adipocyte differentiation by both TGF- and hypoxia-mimetic DFO. Thus, the TGF-/Smad signaling pathway is required for hypoxia-mediated inhibition of adipocyte differentiation in MSCs.

Received for publication, November 16, 2004 , and in revised form, March 25, 2005.

^* This work was supported by Grants AR45870 and AG 025015 from the National Institutes of Health (to J. G.). This work was presented as a plenary poster at the 26th Annual Meeting of the American Society for Bone and Mineral Research, October 1–5, 2004, Seattle, WA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Orthopedic Surgery, Brigham & Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. Tel.: 617-732-5397; Fax: 617-732-6937; E-mail: jglowacki{at}rics.bwh.harvard.edu.

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