Systemic inhibition of BMP1-3 decreases progression of CCl₄-induced liver fibrosis in rats

Abstract

Liver fibrosis is a progressive pathological process resulting in an accumulation of excess extracellular matrix proteins. We discovered that bone morphogenetic protein 1-3 (BMP1-3), an isoform of the metalloproteinase Bmp1 gene, circulates in the plasma of healthy volunteers and its neutralization decreases the progression of chronic kidney disease in 5/6 nephrectomized rats. Here, we investigated the potential role of BMP1-3 in a chronic liver disease. Rats with carbon tetrachloride (CCl)-induced liver fibrosis were treated with monoclonal anti-BMP1-3 antibodies. Treatment with anti-BMP1-3 antibodies dose-dependently lowered the amount of collagen type I, downregulated the expression of Tgfb1, Itgb6, Col1a1, and Acta2 and upregulated the expression of Ctgf, Itgb1, and Dcn. Mehanistically, BMP1-3 inhibition decreased the plasma levels of transforming growth factor beta 1(TGFβ1) by prevention of its activation and lowered the prodecorin production further suppressing the TGFβ1 profibrotic effect. Our results suggest that BMP1-3 inhibitors have significant potential for decreasing the progression of fibrosis in liver cirrhosis.

BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD

“…It has the property of metal protease (matrix metalloproteinases) cutting the COOHterminal of precollagen type I, precollagen type II, and precollagen type III, leading to the maturation of collagens and deposition of the ECM (7,10,12,15). Grgurevic et al (8) reported that BMP1 promotes the cleavage of procollagen type I, resulting in collagen deposition in cirrhosis. In addition, it has also been reported that in the rat model of CKD, BMP1-3 (BMP1 splicing subtype) can promote renal fibrosis by increasing ECM deposition, which was attenuated by specific polyclonal antibody against BMP1ϪBMP3 (9).…”

The Effect of Lecithins Coupled Decorin Nanoliposomes on Treatment of Carbon Tetrachloride-Induced Liver Fibrosis

“…To further study the antifibrotic effect of PC-DCN liposomes, we used rat HSC-T6 astrocytes stimulated with TGF- β to yield active HSC-T6 cells. TGF- β 1, a powerful fibrillary cytokine, stimulates collagen type I expression in primary HSCs [ 15 ]. As shown in Figure 2 , EdU analysis indicated that PC-DCN could significantly inhibit the TGF- β -induced proliferation of HSC-T6 cells ( Figure 2(a) ).…”

The role of bone morphogenetic proteins in liver fibrosis

“…Treatment with anti-BMP1-3, an isoform of BMP1, decreased CCl 4 -induced rat liver fibrosis, evidenced by downregulated ECMs (e.g., collagen type I) and decreased plasma levels of TGF-β1. 27 In comparison to non-cancerous liver fibroblasts (NFs), BMP4 was found up-regulated in cancer-associated fibroblasts (CAFs), which expressed more ECM genes such as ACTA2 (smooth muscle actin alpha 2) and COL1A1 (alpha-1 type I collagen). In addition, overexpression of BMP4 in fibroblasts showed the phenotype and function of CAFs.…”