Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling

Victor W. Wong, Kristine C. Rustad, Satoshi Akaishi, Michael Sorkin, Jason P. Glotzbach, Michael Januszyk, Emily R. Nelson, Kemal Levi, Josemaria Paterno, Ivan N. Vial, Anna A. Kuang, Michael T. Longaker, Geoffrey C. Gurtner

    Research output: Contribution to journalArticle

    211 Scopus citations

    Abstract

    Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood. One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK). Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation. We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders. Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment. These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK-ERK-MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.

    Original languageEnglish (US)
    Pages (from-to)148-152
    Number of pages5
    JournalNature medicine
    Volume18
    Issue number1
    DOIs
    StatePublished - Jan 1 2012

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Wong, V. W., Rustad, K. C., Akaishi, S., Sorkin, M., Glotzbach, J. P., Januszyk, M., Nelson, E. R., Levi, K., Paterno, J., Vial, I. N., Kuang, A. A., Longaker, M. T., & Gurtner, G. C. (2012). Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nature medicine, 18(1), 148-152. https://doi.org/10.1038/nm.2574