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Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats.
Growth Factors ( IF 1.8 ) Pub Date : 2018-02-27 , DOI: 10.1080/08977194.2018.1428966
Lovorka Grgurevic 1, 2 , Igor Erjavec 1 , Ivica Grgurevic 3 , Ivo Dumic-Cule 1 , Jelena Brkljacic 1 , Donatella Verbanac 2 , Mario Matijasic 2 , Hana Cipcic Paljetak 2 , Rudjer Novak 2 , Mihovil Plecko 1 , Jadranka Bubic-Spoljar 2 , Dunja Rogic 4 , Vera Kufner 1 , Martina Pauk 1 , Tatjana Bordukalo-Niksic 1 , Slobodan Vukicevic 1, 3
Affiliation  

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 (CCl4)-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.



中文翻译:

BMP1-3的全身性抑制作用可降低CCl4诱导的大鼠肝纤维化的进程。

肝纤维化是一种进行性病理过程,导致多余的细胞外基质蛋白积聚。我们发现,骨形态发生蛋白1-3(BMP1-3)是金属蛋白酶Bmp1基因的同种型,在健康志愿者的血浆中循环,其中和降低了5/6肾切除大鼠的慢性肾脏疾病的进展。在这里,我们调查了BMP1-3在慢性肝病中的潜在作用。用单克隆抗BMP1-3抗体治疗患有四氯化碳(CCl 4)诱导的肝纤维化的大鼠。抗BMP1-3抗体治疗可剂量依赖性地降低I型胶原的量,下调Tgfb1Itgb6Col1a1,Acta2,并上调Ctgf,Itgb1Dcn的表达。从机理上讲,BMP1-3的抑制通过阻止其活化而降低了转化生长因子β1(TGFβ1)的血浆水平,并降低了前庭素的产生,从而进一步抑制了TGFβ1的纤维化作用。我们的结果表明,BMP1-3抑制剂具有降低肝硬化纤维化进程的巨大潜力。

更新日期:2018-02-27
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