Original Article

You have full text access to this OnlineOpen article

Activation of Transforming Growth Factor-β1/p38/Smad3 Signaling in Stromal Cells Requires Reactive Oxygen Species–Mediated MMP-2 Activity During Bone Marrow Damage

  1. Lin Wang1,
  2. Suzanne Clutter2,
  3. Jonathan Benincosa3,
  4. James Fortney1,
  5. Laura F. Gibson Ph.D.1,2,3,*

Article first published online: 1 SEP 2005

DOI: 10.1634/stemcells.2004-0354

Issue

STEM CELLS

STEM CELLS

Volume 23, Issue 8, pages 1122–1134, September 2005

Additional Information

How to Cite

Wang, L., Clutter, S., Benincosa, J., Fortney, J. and Gibson, L. F. (2005), Activation of Transforming Growth Factor-β1/p38/Smad3 Signaling in Stromal Cells Requires Reactive Oxygen Species–Mediated MMP-2 Activity During Bone Marrow Damage. STEM CELLS, 23: 1122–1134. doi: 10.1634/stemcells.2004-0354

Author Information

  1. 1

    Department of Pediatrics, West Virginia University, School of Medicine, Morgantown, West Virginia, USA

  2. 2

    Department of Microbiology, Immunology, and Cell Biology, West Virginia University, School of Medicine, Morgantown, West Virginia, USA

  3. 3

    Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, School of Medicine, Morgantown, West Virginia, USA

*P.O. Box 9214, Department of Pediatrics, School of Medicine, WV University, Morgantown, West Virginia, 26506, USA. Telephone: 304-293-5820; Fax: 304-293-4341

Publication History

  1. Issue published online: 2 JAN 2009
  2. Article first published online: 1 SEP 2005
  3. Manuscript Accepted: 20 APR 2005
  4. Manuscript Received: 13 DEC 2004

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article (HTML) Get PDF (550K)

Keywords:

  • Transforming growth factor-β1;
  • Smad3;
  • Reactive oxygen species;
  • MMP-2;
  • Chemotherapy;
  • Microenvironment

Abstract

Dose-escalated chemotherapy has proven utility in a variety of treatment settings, including preparative regimens before bone marrow or hematopoietic stem cell transplantation. However, the potential damage imposed by aggressive regimens on the marrow microenvironment warrants further investigation. In the present study, we tested the hypothesis that dose-escalated chemotherapy, with etoposide as a model chemotherapeutic agent, activates the transforming growth factor beta-1 (TGF-β1) signaling pathway in bone marrow stromal cells. After high-dose etoposide exposure in vitro, Smad3 protein was phosphorylated in a time-and dose-dependent manner in marrow-derived stromal cells, coincident with the release of active and latent TGF-β1 from the extracellular matrix. Phosphorylation was modulated by p38 kinase, with translocation of Smad3 from the cytoplasm to the nucleus subsequent to its phosphorylation. Etoposide induced activation of TGF-β1 followed the generation of reactive oxygen species and required matrix metalloproteinase-2 (MMP-2) protein availability. Chemotherapy effects were diminished in MMP-2−/− knockout stromal cells and TGF-β1 knockdown small interfering RNA–transfected stromal cells, in which phosphorylation of Smad3 was negligible after etoposide exposure. Stable transfection of a human MMP-2 cDNA into bone marrow stromal cells resulted in elevated phosphorylation of Smad3 during chemotherapy. These data suggest TGF-β1/p38/Smad3 signaling cascades are activated in bone marrow stromal cells after dose-escalated chemotherapy and may contribute to chemotherapy-induced alterations of the marrow microenvironment.

View Full Article (HTML) Get PDF (550K)