Hepatocyte growth factor inhibits TGF-β1-induced myofibroblast differentiation in tendon fibroblasts: role of AMPK signaling pathway.
The transforming growth factor-β1 (TGF-β1)-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-β1-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-β1-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-β1-induced myofibroblastic differentiation in tendon fibroblasts. Moreover, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 subunit decreased the inhibitory effect of HGF on TGF-β1-induced myofibroblastic differentiation in tendon fibroblasts. Finally, overexpression of constitutively active AMPKα1, which led to constitutive activation of the AMPK signaling pathway in tendon fibroblasts, mimicked the inhibitory effect of HGF on the TGF-β1-induced myofibroblastic differentiation. Our study therefore suggests that HGF inhibits TGF-β1-induced myofibroblastic differentiation via an AMPK signaling pathway-dependent manner in tendon fibroblasts.
Pediatric Orthopedics Unit, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, 150081, China.
Qingbo
Q
Cui
Songbin
S
Fu
Zhaozhu
Z
Li
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D008297:Male; D058628:Myofibroblasts / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013710:Tendons / Q000166:cytology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*
D011720:Pyrazoles; D011743:Pyrimidines; D053773:Transforming Growth Factor beta1; C516138:dorsomorphin; D017228:Hepatocyte Growth Factor; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase