Bone morphogenetic protein–7 (BMP–7), a neglected player in hepatic fibrosis?

Aims: BMP–7 is a member of the TGF-β superfamily, that has been shown to counteract the profibrogenic signaling of TGF-β [1] The supplementation of exogenous recombinant BMP–7 suppresses experimental renal fibrosis [2]. In vitro BMP–7 antagonizes TGF-β1-induced epithelial-to-mesenchymal transition. The expression and putative function of BMP–7 in the process of liver fibrosis, however, has not been analyzed so far. Methods: In the current study we elucidate the expression of BMP–7 by RT-PCR using total liver RNA from bile duct-ligated rats or untreated controls as well as RNA from cultured isolated rat liver cells. Furthermore, we preformed immunohistochemistry with isolated fixed liver cells. The expression of the corresponding BMP–7 receptors, as well as downstream Smad1/5/8 mediators was investigated by RT-PCR in isolated liver cells. The activation of the downstream mediators Smad1/5 was displayed by Western blot using specific antibodies against phospho-Smads and by a selective Smad1/5 reporter, i.e. (BRE)2-Luciferase. Results: We show for the first time, that BMP–7 is expressed in hepatocytes, endothelial cells and Kupffer cells but not in hepatic stellate cells (HSC). Hepatocytes as well as HSC express specific subsets of receptors capable of binding BMP–7 as evaluated by RT-PCR. We further clarified a potential ability of an autocrine stimulus on hepatocytes and paracrine effect of BMP–7 on HSC and portal myofibroblasts by detecting the phosphorylated forms of Smad1/5 and measuring the activity of the (BRE)2-Luc reporter in the respective cells. Conclusions: In conclusion, BMP–7 is expressed by a specific subset of liver cells. Moreover, the most profibrogenic cell type in the liver, the HSC, is responsive towards BMP–7 but do not produce the TGF-β counterpart. Based on the overall hepatoprotective attributes and the here presented data, BMP–7 might be an agent to treat liver fibrosis. This hypothesis is currently, at least in vitro under investigation.

References: [1] Allendorph GP et al. (2006) Proc Natl Acad Sci USA 103: 7643-8. [2] Zeisberg M et al. (2003) Nat Med 9: 964-8.

BMP-7 - hepatic stellate cell - myofibroblasts