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Papers In Press, published online ahead of print April 20, 2005
Orthopedic Research, Brigham and Women's Hospital, Boston, MA 02115
Corresponding Author: jglowacki{at}rics.bwh.harvard.edu
Although hypoxia and TGF-b inhibit differentiation of adipocytes from preadipocytes and marrow-derived cells in several species, the relationship between hypoxia and TGF-b signaling in adipocytogenesis is unknown. In this study, we evaluated the mechanisms of inhibition of adipocyte differentiation by hypoxia and TGF-b in human (h) and murine (m) marrow stromal cells (MSCs), and the role of TGFb/Smad signaling in the inhibition of adipocytogenesis by hypoxia. Both the hypoxia-mimetic deferoxamine mesylate (DFO) and TGF-b1 inhibited adipocyte differentiation (1.0% vs. control at 15 mM DFO; 1.4% vs. control at 1 ng/ml TGF-b1) and adipocyte gene expression (PPARg2 and LPL) in hMSCs (21 days of treatment). Hypoxia (2% O2) and DFO, but not TGF-b1, increased hypoxia-inducible factor-1 (HIF-1a), as shown by Western blot. Macroarray, Western and Northern blot analyses showed that hypoxia activated the TGF-b/Smad signaling pathway, and that both hypoxia and TGF-b1 modulated adipocyte differentiation pathways, such as the insulin, PPARg, PI-3 kinase, and MAPK-associated signaling pathways. Studies with mouse marrow stromal cell lines derived from Smad3+/+ or Smad3-/- mice revealed that TGF-b type I receptor (ALK-5) and its intracellular signal molecule Smad3 were necessary for inhibition of adipocyte differentiation by both TGF-b and the hypoxia-mimetic DFO. Thus, the TGF-b/Smad signaling pathway is required for hypoxia-mediated inhibition of adipocyte differentiation in MSCs.
J. Biol. Chem, 10.1074/jbc.M412953200
Submitted on November 16, 2004
Accepted on April 20, 2005
Hypoxia inhibition of adipocytogenesis in human bone marrow stromal cells requires TGFbeta/Smad3 signaling
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