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

Ryoichi Mori, Tanya J Shaw, Paul Martin

Research output: Contribution to journalArticlepeer-review

241 Citations (Scopus)

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-Rbeta-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.
Original languageEnglish
Pages (from-to)43-51
Number of pages9
JournalThe Journal of experimental medicine
Volume205
Issue number1
DOIs
Publication statusPublished - 21 Jan 2008

Keywords

  • 3T3 Cells
  • Animals
  • Cicatrix
  • Extracellular Matrix
  • Fibroblasts
  • Fibrosis
  • Inflammation
  • Integrin-Binding Sialoprotein
  • Leukocytes
  • Macrophages
  • Mast Cells
  • Mice
  • Models, Biological
  • Neutrophils
  • Oligonucleotides, Antisense
  • Osteopontin
  • Rats
  • Sialoglycoproteins
  • Wound Healing

Fingerprint

Dive into the research topics of 'Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring'. Together they form a unique fingerprint.

Cite this