1. Division of Gastroenterology and Institute of Digestive Disease, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
2. Division of Gastroenterology, East Hospital of Tongji University School of Medicine, Shanghai 200120, China;
3. Special Outpatient Clinic, The Affiliated Hospital of Medical College Qingdao University, Qingdao 266003, China.
Background/Aims: Transforming growth factor-β1 (TGF-β1) plays an important role in the pathogenesis of liver fibrosis and cirrhosis. Recombinant human bone morphogenic protein-7 (rhBMP-7) alleviates renal fibrosis and improves kidney function. However, the beneficial effect of BMP-7 on hepatic fibrosis and cirrhosis remains unknown. The purpose of this study was to investigate the prophylactic and therapeutic effects of rhBMP-7 on liver fibrosis and the underlying mechanisms.
Methods: Liver fibrosis in the rat model was induced by peritoneal injection of porcine-serum (0.5ml/kg body weight) twice a week over 8 weeks. The effect of rhBMP-7 on hepatic fibrosis was monitored in rhBMP-7 pre-treated and non-treated rats. Pathologic changes were determined by immunohistolocial staining. TGF-β1 expression was investigated by immunohistolocial staining, western blotting, and real-time PCR. Collagen secretion was measured by enzyme-linked immunosorbent assay.
Results: Liver fibrosis was significantly reduced by rhBMP-7. The secretion of collagen type-I and -III was decreased by rhBMP-7 in hepatic stellate cells (HSCs) but not in hepatocytes. The anti-fibrotic effect of rhBMP-7 on liver fibrosis was resulted by blocking the nuclear accumulation of Smad2/3 or by inhibiting TGF-β1 expression in HSCs or hepatocytes.
Conclusions: The anti-fibrogenic mechanism of rhBMP-7 in the rat liver fibrosis was depended on the reduction of TGF-β1 overexpression and the inhibition of TGF-β1 triggered intracellular signalling in hepatic cells.
Keywords: liver fibrosis, hepatic stellate cell, hepatocytes, bone morphogenic protein-7, transforming growth factor beta 1, epithelial-to-mesenchymal transition, extracellular matrix.