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

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.

Regulation of epithelial to mesenchymal transition by bone morphogenetic proteins

“…In a mouse model of bleomycin-induced fibrosis, systemically administered recombinant BMP7 did not affect fibrosis in either the lung or skin and no effect on expression of pro-fibrotic genes by lung fibroblasts was observed [67]. This suggests that BMP7 may have diverse, even opposing, roles in different tissues.…”

Gremlin1 preferentially binds to bone morphogenetic protein-2 (BMP-2) and BMP-4 over BMP-7

“…BMP-7 is thought of as anti-fibrotic, and has been the focus of many groups who demonstrated its anti-fibrotic activity in models of diabetic nephropathy and other kidney fibrotic diseases [5,[12][13][14][15][16][17]. To date, however, efforts to translate these data into BMP-7-centred treatment of fibrosis have been rather slow to develop [18,19] Canonical BMPs signalling involves the Smad pathway, where BMP dimers bind to type I and type II BMP receptors leading to the formation of a hexameric complex, triggering receptor phosphorylation. This leads to phosphorylation of R-Smads (Smad1/5/8) and complex formation with co-Smad4 which translocates to the nucleus to regulate BMP target gene expression [1,2].…”

A neutrophil elastase inhibitor prevents bleomycin-induced pulmonary fibrosis in mice

“…Recent studies have suggested that increased collagen turnover and fibrotic changes are earlier events within 14 days in the BLMinduced fibrosis [8][9][10][11] and these changes were used commonly as a pulmonary fibrosis model. Signs of fibrosis were observed at 7 days after BLM administration [8].…”