FR-167653, a selective p38 MAPK inhibitor, exerts salutary effect on liver cirrhosis through downregulation of Runx2

Abstract

Liver cirrhosis remains a difficult-to-treat disease with a substantial morbidity and mortality rate. There is an emerging body of data purporting a pivotal role of the activated p38 mitogen-activated protein kinase (MAPK) in the process of cirrhosis. Several anticirrhotic agents have been developed over the past few years, and most of them exert their effects by indirectly inhibiting the p38 pathway. Effect of a selective p38 inhibitor is yet to be reported. In this study, we evaluated the salutary effect of FR-167653 (FR), a selective p38 inhibitor, in a carbon tetrachloride (CCl 4 )-induced rat cirrhotic model. Twenty rats were assigned into four groups: Sham, olive oil only; Control, CCl 4 in olive oil; FR50, FR 50 mg/ kg/day and CCl 4 ; and FR100, FR 100 mg/kg/day and CCl 4 . FR dose-dependently inhibited activation of p38 and had an ameliorating effect on cirrhosis formation. Significant dose-dependent reduction in a-smooth muscle actin immunostaining and hydroxyproline content of the liver was noticed in the FR-treated rats. Also densitometric analysis showed a significant reduction in azan-stained area in the FR-treated rats. These fibrotic changes were observed in the myofibroblasts including the hepatic stellate cells and portal fibroblasts. mRNA expression of runt-related protein 2 (Runx2), a profibrogenic transcription factor, was significantly low in FR-treated livers, indicating that Runx2 might be a key downstream regulator of the p38 pathway. A similar reduction in expression of Smad4 and tissue inhibitor of metalloproteinase-1 was noticed in the FR-treated rats. In conclusion, FR treatment exerted a significant beneficial effect in a CCl 4 -induced rat cirrhotic model. The ameliorating effect of FR could be partially attributable to an inhibition of the Smad4/p38/Runx2 axis in the cirrhotic liver.

Hepatic Osteodystrophy: The Mechanism of Bone Loss in Hepatocellular Disease and the Effects of Pamidronate Treatment

“…There is no clear explanation for this occurrence, but in a previous study, it was observed that RUNX-2 expression was elevated in the livers of cirrhotic mice previously treated with CCl 4 29. The study called attention to RUNX-2 regulating collagen synthesis, demonstrating that myofibroblasts, including hepatic stellate cells and portal fibroblasts, express RUNX-2 29. This insightful study indicated that CCl 4 could up-regulate RUNX-2 in mesenchymal cells, unlike in osteoblasts 29.…”

“…However, after disodium pamidronate treatment, the significant increase in the expression of RUNX2 in bone was restricted to animals treated with CCl 4 . There is no clear explanation for this occurrence, but in a previous study, it was observed that RUNX-2 expression was elevated in the livers of cirrhotic mice previously treated with CCl 4 29. The study called attention to RUNX-2 regulating collagen synthesis, demonstrating that myofibroblasts, including hepatic stellate cells and portal fibroblasts, express RUNX-2 29.…”

Effects of dahuangzhechong pills on cytokines and mitogen activated protein kinase activation in rats with hepatic fibrosis

“…p38 MAPK was found independently increase ␣ 1 (I) collagen expression at transcriptional level. Additionally, both MAPK kinase (MKK) 3 and MKK6, two upstream kinases involved in activating p38 MAPK, have been shown to activate p38 MAPK in HSCs, which was associated with enhanced collagen expression in HSCs p38 MAPK is also found to increase the stability of ␣ 1 (I) collagen mRNA in untreated and activated HSCs (Cao et al, 2006;Hattori et al, 2007;Parsons et al, 2007). The secretion of type I collagen in acetaldehyde-induced HSCs are markedly inhibited by PD98059, a specific MEK inhibitor.…”

Fluorescently Labeled Nanoparticles Enable the Detection of Stem Cell-Derived Hepatocytes

“…5 For this reason, liver cirrhosis is a disease that is difficult to treat and has a substantial morbidity and mortality rate. 6 In fact, treatment options for liver cirrhosis are very limited. 2 To date, there is no treatment available to reverse liver cirrhosis.…”