Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 176, Issue 3, Pages 1215-1228Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2010.090802
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- Research into Ageing
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Fibroblast differentiation into myofibroblasts is a key event during normal wound repair. We have previously demonstrated an age-related defect in this process associated with impaired synthesis of hyaluronan (HA) synthase (HAS) 2 but failed to prescribe its role in a mechanistic sense. Here we demonstrate that in addition to HAS2, there is loss of EGF receptor (EGF-R) in aged cells, and both are required for normal fibroblast functionality. Analysis of molecular events revealed that in young cells, transforming growth factor (TGF)-beta 1-dependent phenotypic activation uses two distinct but cooperating pathways that involve TGF-beta receptor/Smad2 activation and EGF-mediated EGF-R/extracellular signal-regulated kinase (ERK) 1/2 signaling, and the latter is compromised with in vitro aging. Pharmacological inhibition of any of the five intermediates (TGF-beta receptor, Smad2, EGF, EGF-R, and ERK1/2) attenuated TGF-beta 1 induction of alpha-smooth muscle actin. We present evidence that the HA receptor CD44 co-immunoprecipitates; with EGF-R after activation by TGF-beta 1. This interaction is HA-dependent because disruption of HA synthesis abrogates this association and inhibits subsequent ERK1/2 signaling. in aged fibroblasts, this association is lost with resultant suppression of ERK1/2 activation. Forced overexpression of EGF-R and HAS2 in aged cells restored TGF-beta 1-mediated HA-CD44/EGF-R association and alpha-smooth muscle actin induction. Taken together, these results demonstrate that HA can serve as a signal integrator by facilitating TGF-beta 1-mediated CD44-EGF-R-ERK interactions and ultimately fibroblast phenotype. We propose a model to explain this novel mechanism and the functional consequence of age-dependent dysregulation. (Am J Pathol 2010, 176:1215-1228 DOI: 10.2353/ajpath.2010.090802)
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