Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury

Nature Medicine volume 9, pages 964–968 (2003)Cite this article

Abstract

Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-β superfamily1. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development2. Here we report that BMP-7 reverses TGF-β1–induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule3. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-β1–induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-β1–induced de novo EMT in a mouse model of chronic renal injury4. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-β1 in the regulation of EMT in health and disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: E-cadherin expression in renal tubular epithelial cells.
Figure 2: Regulation of E-cadherin promoter activity.
Figure 3: Reversal of chronic renal injury by BMP-7 in mouse NTN.
Figure 4: Smad-associated reversal of EMT in vivo.

Similar content being viewed by others

References

  1. Ozkaynak, E. et al. OP-1 cDNA encodes an osteogenic protein in the TGF-beta family. EMBO J. 9, 2085–2093 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hogan, B.L. Bone morphogenetic proteins in development. Curr. Opin. Genet. Dev. 6, 432–438 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Cano, A. et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2, 76–83 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Thiery, J.P. Epithelial-mesenchymal transitions in tumor progression. Nat. Rev. Cancer 2, 442–454 (2002).

    Article  CAS  PubMed  Google Scholar 

  6. Hay, E.D. & Zuk, A. Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. Am. J. Kidney Dis. 26, 678–690 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Strutz, F. et al. Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 61, 1714–1728 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Behrens, J., Lowrick, O., Klein-Hitpass, L. & Birchmeier, W. The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. Proc. Natl. Acad. Sci. USA 88, 11495–11499 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heldin, C.H., Miyazono, K. & ten Dijke, P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature 390, 465–471 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Wrana, J.L. Regulation of Smad activity. Cell 100, 189–192 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Derynck, R., Zhang, Y. & Feng, X.H. Smads: transcriptional activators of TGF-beta responses. Cell 95, 737–740 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Massague, J. How cells read TGF-beta signals. Nat. Rev. Mol. Cell. Biol. 1, 169–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Attisano, L. & Wrana, J.L. Signal transduction by the TGF-beta superfamily. Science 296, 1646–1647 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Chen, Y.G. et al. Determinants of specificity in TGF-beta signal transduction. Genes Dev. 12, 2144–2152 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ishida, W. et al. Smad6 is a Smad1/5-induced smad inhibitor. Characterization of bone morphogenetic protein-responsive element in the mouse Smad6 promoter. J. Biol. Chem. 275, 6075–6079 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Candia, A.F. et al. Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads. Development 124, 4467–4480 (1997).

    CAS  PubMed  Google Scholar 

  17. Comijn, J. et al. The two-handed E box binding zinc finger protein SIP1 downregulates E- cadherin and induces invasion. Mol. Cell 7, 1267–1278 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Lloyd, C.M. et al. RANTES and monocyte chemoattractant protein-1 (MCP-1) play an important role in the inflammatory phase of crescentic nephritis, but only MCP-1 is involved in crescent formation and interstitial fibrosis. J. Exp. Med. 185, 1371–1380 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hruska, K.A. et al. Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction. Am. J. Physiol. Renal Physiol. 279, F130–F143 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Border, W.A. et al. Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 360, 361–364 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Remuzzi, G. & Bertani, T. Pathophysiology of progressive nephropathies. N. Engl. J. Med. 339, 1448–1456 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Hennig, G., Lowrick, O., Birchmeier, W. & Behrens, J. Mechanisms identified in the transcriptional control of epithelial gene expression. J. Biol. Chem. 271, 595–602 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Kawabata, M., Inoue, H., Hanyu, A., Imamura, T. & Miyazono, K. Smad proteins exist as monomers in vivo and undergo homo- and hetero- oligomerization upon activation by serine/threonine kinase receptors. EMBO J. 17, 4056–4065 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Imamura, T. et al. Smad6 inhibits signalling by the TGF-beta superfamily. Nature 389, 622–626 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Okada, H., Danoff, T.M., Kalluri, R. & Neilson, E.G. Early role of Fsp1 in epithelial-mesenchymal transformation. Am. J. Physiol. 273, F563–F574 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Zeisberg, M. et al. Renal fibrosis: collagen composition and assembly regulates epithelial-mesenchymal transdifferentiation. Am. J. Pathol. 159, 1313–1321 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hanai, J. et al. Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline C alpha promoter. J. Biol. Chem. 274, 31577–31582 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Zeisberg, M., Maeshima, Y., Mosterman, B. & Kalluri, R. Renal fibrosis: extracellular matrix microenvironment regulates migratory behavior of activated tubular epithelial cells. Am. J. Pathol. 160, 2001–2008 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by National Institutes of Health grants DK 51711, DK 55001, T32 DK07199-25, Deutsche Forschungsgemeinschaft grant DFG ZE523/1-1 (to M.Z.) and Beth Israel Deaconess Medical Center funds associated with the Center for Matrix Biology. We thank Creative Biomolecules/Curis, Inc. for the recombinant human BMP-7; V.P. Sukhatme for introducing us to Creative Biomolecules/Curis, Inc. when he served as their consultant; and L. Siniski and A. Zuk for their help with the preparation of this manuscript; F.S. was a visiting scientist at Beth Israel Deaconess Medical Center and Harvard Medical School during the course of this study.

Author information

Author notes

  1. Michael Zeisberg and Jun-ichi Hanai: These authors contributed equally to this work.

Authors and Affiliations

  1. Gastroenterology and Renal Divisions, Department of Medicine, Center for Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02215, Massachusetts, USA

    Michael Zeisberg, Jun-ichi Hanai, Hikaru Sugimoto, Tadanori Mammoto, David Charytan, Frank Strutz & Raghu Kalluri

Authors
  1. Michael Zeisberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun-ichi Hanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hikaru Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tadanori Mammoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Charytan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frank Strutz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Raghu Kalluri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raghu Kalluri.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zeisberg, M., Hanai, Ji., Sugimoto, H. et al. BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9, 964–968 (2003). https://doi.org/10.1038/nm888

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm888

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
  NODES
admin 1
Association 1
INTERN 1
Note 1
twitter 1