Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring

Mori, Ryoichi, Shaw, Tanya J. and Martin, Paul ORCID: https://orcid.org/0000-0002-2665-5086 2008. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. Journal of Experimental Medicine 205 (1) , pp. 43-51. 10.1084/jem.20071412

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Abstract

Previous studies of tissue repair have revealed osteopontin (OPN) to be up-regulated in association with the wound inflammatory response. We hypothesize that OPN may contribute to inflammation-associated fibrosis. In a series of in vitro and in vivo studies, we analyze the effects of blocking OPN expression at the wound, and determine which inflammatory cells, and which paracrine factors from these cells, may be responsible for triggering OPN expression in wound fibroblasts. Delivery of OPN antisense oligodeoxynucleotides into mouse skin wounds by release from Pluronic gel decreases OPN protein levels at the wound and results in accelerated healing and reduced granulation tissue formation and scarring. To identify which leukocytic lineages may be responsible for OPN expression, we cultured fibroblasts in macrophage-, neutrophil-, or mast cell–conditioned media (CM), and found that macrophage- and mast cell–secreted factors, specifically platelet-derived growth factor (PDGF), induced fibroblast OPN expression. Correspondingly, Gleevec, which blocks PDGF receptor signaling, and PDGF-Rβ–neutralizing antibodies, inhibited OPN induction by macrophage-CM. These studies indicate that inflammation-triggered expression of OPN both hinders the rate of repair and contributes to wound fibrosis. Thus, OPN and PDGF are potential targets for therapeutic modulation of skin repair to improve healing rate and quality.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Additional Information:	Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0022-1007/ (accessed 12/03/2014).
Publisher:	Rockefeller University Press
ISSN:	0022-1007
Date of First Compliant Deposit:	30 March 2016
Last Modified:	05 May 2023 03:12
URI:	https://orca.cardiff.ac.uk/id/eprint/48477

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