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.

Bone Morphogenetic Protein 9 Is a Paracrine Factor Controlling Liver Sinusoidal Endothelial Cell Fenestration and Protecting Against Hepatic Fibrosis

“…Intriguingly, two independent teams recently reported that administration of BMP9 to mice that develop chemically induced (by CCl 4 or lipopolysaccharide [LPS]) hepatic fibrosis potentiates this fibrogenic response, whereas BMP9 neutralization reduces the severity of liver disease . In one of these studies, the initial effect of either CCl 4 or LPS injection in mice was a decrease in circulating BMP9 levels, which was then followed by a rebound peak of BMP9 between 24 and 48 hours after injection .…”

“…When analyzing two distinct publicly available human data sets, the same team reported that BMP9 expression was not significantly changed in the livers of hepatitis B virus–related patients with increasing fibrosis stages . In contrast, Li et al observed a direct correlation between the serum levels of BMP9 and the stage of fibrosis in a limited series of patients with liver fibrosis . More recently, analysis of distinct transcriptomic data sets from those mentioned above revealed that hepatic BMP9 mRNA expression is decreased in several human liver diseases including cirrhosis, nonalcoholic steatohepatitis, and hepatocarcinomas .…”

Combined Ultrasound and Nerve Stimulator-Guided Deep Nerve Block May Decrease the Rate of Local Anesthetics Systemic Toxicity: A Randomized Clinical Trial

“…Higher BMP-9 levels in human serum are accompanied by advanced stages of liver fibrosis, while BMP-9 overexpression accelerated liver fibrosis and BMP-9 knockdown attenuated the liver fibrosis in a mouse model [31]. The plasma VEGF level was elevated in patients with cirrhosis, especially in those with spider angiomas [27].…”

Combined Ultrasound and Nerve Stimulator-Guided deep nerve block may decrease the rate of local anesthetics systemic toxicity: A Randomized clinical trial

“…Higher BMP-9 levels in human serum are accompanied by advanced stages of liver fibrosis, while BMP-9 overexpression accelerated the liver fibrosis and BMP-9 knockdown attenuated the liver fibrosis in a mouse model [31]. The plasma VEGF level was elevated in patients with cirrhosis, especially in those with spider angiomas [27].…”