Hepatocyte growth factor inhibits TGF-?21-induced myofibroblast differentiation in tendon fibroblasts: role of AMPK signaling pathway

摘要

The transforming growth factor-?21 (TGF-?21)-induced myofibroblastic differentiation in tendon fibroblasts was thought to be one of the most important features of scar fibrosis formation, which is associated with occurrence of re-rupture. Previously, we reported that hepatocyte growth factor (HGF) inhibited TGF-?21-induced myofibroblast differentiation and extracellular matrix deposition in the Achilles tendon of rats. Here, we investigated the potential molecular mechanisms underlying the inhibitory effect of HGF on TGF-?21-induced myofibroblast differentiation. We found that treatment with HGF (10, 20, and 40??ng/ml) increased phosphorylation of adenosine monophosphate kinase (AMPK) and acetyl-CoA carboxylase (ACC) in tendon fibroblasts. Pharmacological inhibition of the AMPK signaling pathway using compound C, a specific blocker of AMPK signaling, remarkably attenuated the inhibitory effect of HGF on TGF-?21-induced myofibroblastic differentiation in tendon fibroblasts. Moreover, small interfering RNA (siRNA)-mediated knockdown of AMPK?±1 subunit decreased the inhibitory effect of HGF on TGF-?21-induced myofibroblastic differentiation in tendon fibroblasts. Finally, overexpression of constitutively active AMPK?±1, which led to constitutive activation of the AMPK signaling pathway in tendon fibroblasts, mimicked the inhibitory effect of HGF on the TGF-?21-induced myofibroblastic differentiation. Our study therefore suggests that HGF inhibits TGF-?21-induced myofibroblastic differentiation via an AMPK signaling pathway-dependent manner in tendon fibroblasts.