Targeting secreted cytokine BMP9 gates the attenuation of hepatic fibrosis

Abstract

Liver fibrosis is overly exuberant wound healing that leads to portal hypertension or liver cirrhosis. Recent studies have demonstrated the functions of bone morphogenetic protein 9 (BMP9) in liver fibrosis, and thus, targeting liver-specific BMP9 abnormalities will become an attractive approach for developing therapeutics to treat liver fibrosis. Here, we reveal that BMP9 serves as a valuable serum diagnostic indicator and efficient therapeutic target to attenuate liver fibrogenesis. Our analysis of biopsies from liver fibrotic patients revealed that higher BMP9 levels accompanied advanced stages of liver fibrosis. In mouse models, recombinant Bmp9 overexpression accelerated liver fibrosis, and adenovirus-mediated Bmp9 knockdown attenuated liver fibrogenesis. Intriguingly, BMP9 directly stimulated hepatic stellate cell activation via the SMAD signaling pathway to enhance hepatic fibrosis. Moreover, an inhibitory monoclonal antibody targeting Bmp9 was efficacious in treatment of mice with liver fibrosis. These observations delineate a novel model in which BMP9 directly drives SMAD/ID1 signaling in hepatic stellate cells, which modulates liver fibrogenesis development. Moreover, the findings unveil a promising surrogate biomarker for the diagnosis of hepatic fibrosis, thereby representing an efficient “BMP9 neutralization” approach in alleviating hepatic fibrosis.