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

Nature Medicine volume 18, pages 148–152 (2012)Cite this article

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Abstract

Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood1. 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)1,2. 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 disorders3,4,5. 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.

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Figure 1: HTS model.
Figure 2: Fibroblast-specific MCP-1 pathways.
Figure 3: FAK-mediated mechanoresponsive pathways in human fibroblasts.
Figure 4: Intradermal treatment with PF573228.

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Acknowledgements

We thank B. de Crombrugghe (The University of Texas MD Anderson Cancer Center, Houston, Texas) for providing the procollagen-α2(I)-Cre transgenic mice, J. Rajadas for experimental insight, F. You for harvesting human fibroblasts and Y. Park for histologic processing. This work was supported by the Oak Foundation, the Hagey Family Endowed Fund in Stem Cell Research and Regenerative Medicine and a United States Armed Forces Institute of Regenerative Medicine grant (DOD #W81XWH-08-2-0033).

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Authors and Affiliations

  1. Department of Surgery, Stanford University, Stanford, California, USA

    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, Michael T Longaker & Geoffrey C Gurtner

  2. Oregon Health and Science University Department of Surgery, Portland, Oregon, USA

    Anna A Kuang

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  1. Victor W Wong
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Contributions

V.W.W. and G.C.G. designed the research. V.W.W., M.J. and J.P. analyzed the microarray data. J.P. and I.N.V. generated the FAK knockout mice. V.W.W. and K.C.R. performed the in vitro human fibroblast experiments. V.W.W. and S.A. performed the small molecule injection experiments. V.W.W., K.C.R., M.S., J.P.G. and E.R.N. performed and analyzed the in vivo data. V.W.W. and K.L. performed and analyzed the biomechanics data. A.A.K. provided reagents. V.W.W., K.C.R., M.J. and G.C.G. analyzed data. K.C.R., J.P.G., M.J. and M.T.L. helped prepare the manuscript. V.W.W. and G.C.G. wrote the manuscript.

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Correspondence to Geoffrey C Gurtner.

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The authors declare no competing financial interests.

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Wong, V., Rustad, K., Akaishi, S. et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med 18, 148–152 (2012). https://doi.org/10.1038/nm.2574

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