Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling
Open accessAbstract
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.
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Blocking steps in the FAK-ERK/CCL2 inflammatory pathway reduces scarring in mice.
“Blocking any of these steps leads to reduced scarring in mice (108)”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [108]
FAK-ERK signaling activated by wound biomechanics causes wound fibroblasts to release chemokine ligand 2, which recruits a larger inflammatory response.
“as a wound gapes open and then begins to contract, focal adhesion kinase/extracellular signal–regulated kinase (FAK-ERK) leads to activation of chemokine ligand 2 release by wound fibroblasts, which, in turn, draws in a larger inflammatory response (108).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [108]
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Self-citation
- Authors
- 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.
- Affiliations
- Stanford Medicine (US)
- Oregon Health & Science University (US)
- Corresponding author
- Gurtner, Geoffrey C
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-12-11
- Volume
- 18
- Issue
- 1
- Pages
- 148-152
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4457506
- OpenAlex
- W1992686988
- Cited by
- 515
- References
- 32
- Citations by year
- 2026: 41 · 2025: 36 · 2024: 40 · 2023: 25 · 2022: 57 · 2021: 55 · 2020: 33 · 2019: 32 · 2018: 32 · 2017: 37 · 2016: 26 · 2015: 37 · 2014: 24 · 2013: 28 · 2012: 9
- FWCI
- 26.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG025016)
- U.S. National Library of Medicine (T15LM007033)
- Topics
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- focal adhesion kinase, hypertrophic scars, skin fibrosis, mechanotransduction, mechanical forces, extracellular signal-regulated kinase, MCP-1, inflammation, fibroblast proliferation, wound healing, chemokine signaling, FAK inhibition
- MeSH terms
- Animals, Cells, Cultured, Fibroblasts, Fibrosis, Humans, Mice, Transgenic, Skin, Signal Transduction, Gene Expression, Cicatrix, Hypertrophic, Mice, Knockout, Chemokine CCL2, MAP Kinase Signaling System, Mechanotransduction, Cellular, Mice, Focal Adhesion Protein-Tyrosine Kinases
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