engleski

1037 BMP7 PROTEIN AND BMP1-3 ANTIBODY PREVENT DEVELOPMENT AND PROMOTE REGRESSION OF CCL4- INDUCED LIVER FIBROSIS IN RATS

Aims: To analyze the role of bone morphogenetic protein-7 (BMP7) and BMP1 during the development and regression of liver fibrosis (LF). While the function and source of BMP7 as a important protein involved in the liver organogenesis are known, some controversies exist regarding its role in liver fibrogenesis. The function of BMP1 in liver homeostasis and pathogenesis has not been explored. As BMP1 is the key regulatory enzyme in extracellular matrix biology, its circulating active isoform BMP1–3 might also have prominent role in LF. Materials and Methods: We used experimental model of CCl4- induced (10% solution administrated intraperitonealy) LF in rats. In the prevention arm of the study the animals (8 per group) were treated with: BMP7 protein, BMP1–3 antibody (BMP1–3Ab) or their combination, along with CCl4 for 14 weeks. In the therapeutic arm the same therapy had been administrated for 4 weeks to rats with already established liver cirrhosis (LC), following the withdrawal of CCl4. Extent of LF was assessed by histology (stage od LF) and morphometric analyses (collagen percentage area (CPA%) ; Sirius red staining). Gene expression analyses were performed by qRT-PCR, and protein expression by immunohistochemistry. Results: BMP1–3 was expressed in hepatocytes and sinusoidal endothelial cells, which led us to assume that liver might be the source of circulating BMP1–3. Both bmp1 and bmp7 genes were significantly upregulated in cirrhotic livers but significantly suppressed in the recovery phase. Administration of BMP7 (300 mg/kg) or BMP1–3Ab (15 mg/kg), or their combination resulted in the signifficant reduction of the liver collagen amount compared to animals treated with CCl4 only (3.52±1.91 ; 4.74±0.62 ; 4.61±0.47 and 7.34±2.07 CPA% respectivelly ; p < 0.001). However, only BMP7 and the combination therapy prevented the development of LC in some animals. In rats with already established LC the most pronounced regression of fibrosis was observed upon administration of BMP7 monotherapy or a combination of BMP7 and BMP1–3Ab (2.5 mg/kg) compared to animals with no therapy (3.8±1.1 ; 5.48±0.98 and 6.97±0.96 CPA% respectivelly p < 0.001). Conclusion: Both BMP1 and BMP7 have important role during LF development and regression. BMP7 protein and BMP1– 3Ab successfully suppressed liver fibrogenesis representing a potentialy new antifibrotic and regenerative therapy.

BMP7 ; BMP1-3 ; Liver fibrosis

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