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Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring -- Mori et al. 205 (1): 43 -- The Journal of Experimental Medicine
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Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring
Ryoichi Mori1,2,
Tanya J. Shaw1, and
Paul Martin1,21 Departments of Physiology and 2 Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK
CORRESPONDENCE Paul Martin: paul.martin{at}bristol.ac.uk
Previous studies of tissue repair have revealed osteopontin(OPN) to be up-regulated in association with the wound inflammatoryresponse. We hypothesize that OPN may contribute to inflammation-associatedfibrosis. In a series of in vitro and in vivo studies, we analyzethe effects of blocking OPN expression at the wound, and determinewhich inflammatory cells, and which paracrine factors from thesecells, may be responsible for triggering OPN expression in woundfibroblasts. Delivery of OPN antisense oligodeoxynucleotidesinto mouse skin wounds by release from Pluronic gel decreasesOPN protein levels at the wound and results in accelerated healingand reduced granulation tissue formation and scarring. To identifywhich leukocytic lineages may be responsible for OPN expression,we cultured fibroblasts in macrophage-, neutrophil-, or mastcell–conditioned media (CM), and found that macrophage-and mast cell–secreted factors, specifically platelet-derivedgrowth factor (PDGF), induced fibroblast OPN expression. Correspondingly,Gleevec, which blocks PDGF receptor signaling, and PDGF-R–neutralizingantibodies, inhibited OPN induction by macrophage-CM. Thesestudies indicate that inflammation-triggered expression of OPNboth hinders the rate of repair and contributes to wound fibrosis.Thus, OPN and PDGF are potential targets for therapeutic modulationof skin repair to improve healing rate and quality.
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