BMP-7 Does Not Protect against Bleomycin-Induced Lung or Skin Fibrosis

Lynne A. Murray,Rochelle L. Argentieri,Paul Dudas,Stephanie M. Warner,Tillie L. Hackett,Darryl A. Knight,Francis X. Farrell,Furquan Shaheen,Oliver Eickelberg

doi:10.1371/journal.pone.0004039

Lynne A. Murray, Rochelle L. Argentieri + Show 7 more

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https://doi.org/10.1371/journal.pone.0004039

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Journal: PloS one	Publication Date: Dec 29, 2008
Citations: 65	License type: CC BY 4.0

Affiliation: St. Paul's Hospital, University of British Columbia

Abstract

Bone morphogenic protein (BMP)-7 is a member of the BMP family which are structurally and functionally related, and part of the TGFβ super family of growth factors. BMP-7 has been reported to inhibit renal fibrosis and TGFβ1-induced epithelial-mesenchymal transition (EMT), in part through negative interactions with TGFβ1 induced Smad 2/3 activation. We utilized in vivo bleomycin-induced fibrosis models in the skin and lung to determine the potential therapeutic effect of BMP-7. We then determined the effect of BMP-7 on TGFβ1-induced EMT in lung epithelial cells and collagen production by human lung fibroblasts. We show that BMP-7 did not affect bleomycin-induced fibrosis in either the lung or skin in vivo; had no effect on expression of pro-fibrotic genes by human lung fibroblasts, either at rest or following exposure to TGFβ1; and did not modulate TGFβ1 -induced EMT in human lung epithelial cells. Taken together our data indicates that BMP-7 has no anti-fibrotic effect in lung or skin fibrosis either in vivo or in vitro. This suggests that the therapeutic options for BMP-7 may be confined to the renal compartment.

Highlights

Heightened activation, altered phenotype and augmented synthetic activity of collagen producing cells are hallmarks of fibrosis
We show that recombinant human BMP-7 (rhBMP-7): (1) did not affect bleomycin-induced fibrosis in either the lung or skin in vivo; (2) had no effect on expression of pro-fibrotic genes by human lung fibroblasts, either at rest or following exposure to TGFb1; (3) did not modulate TGFb1 -induced epithelial to mesenchymal transition (EMT) in human lung epithelial cells in vitro
We found increased Bone morphogenic protein (BMP)-7 protein expression following intratracheal bleomycin, we hypothesized that the magnitude of BMP-7 induction is insufficient to modulate TGFb1 activity in the lung

Summary

Introduction

Heightened activation, altered phenotype and augmented synthetic activity of collagen producing cells are hallmarks of fibrosis. TGFb1, is the prototypical pro-fibrotic cytokine and is overexpressed in fibrosis in multiple human settings and animal models [3,4,5]. This growth factor induces excess extracellular matrix (ECM) generation, enhanced fibroblast survival and the differentiation of fibroblasts to aSMA-positive myofibroblasts, which are relatively absent from normal lungs [1,2,3]. Several recent studies have shown that EMT occurs in lung epithelial cells both in vitro and in vivo, supporting the concept of EMT contributing to the fibrosis observed in IPF [5,13,14]. Intracellular processes that modify fibrotic pathways and EMT in particular, have not been evaluated

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