Loss of Keratinocyte Focal Adhesion Kinase Stimulates Dermal Proteolysis Through Upregulation of MMP9 in Wound Healing

Wong, Victor W.; Garg, Ravi; Sorkin, Michael; Rustad, Kristine C.; Akaishi, Satoshi; Levi, Kemal; Nelson, Emily R.; Tran, Misha C.; Rennert, Robert C.; Liu, Wei; Longaker, Michael T.; Dauskardt, Reinhold H.; Gurtner, Geoffrey C.

doi:10.1097/sla.0000000000000219

Cited by 36 publications

(39 citation statements)

References 57 publications

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“…It remains to be fully elucidated which specific inflammatory cell functions are altered by FAK expression during wound healing. In contrast to global FAK inhibition, we recently reported that transgenic mice with loss of keratinocyte-specific FAK displayed enhanced dermal proteolysis and delayed healing of excisional wounds (Wong et al, 2014). This suggests that FAK-mediated signaling is more complex than previously appreciated and shows the importance of mechanical signaling in a variety of cell types.…”

Section: Discussionmentioning

confidence: 94%

“…Fibroblast-specific deletion of FAK in knockout mice displayed substantially reduced inflammation and fibrosis in an incisional HTS model (Wong et al, 2011a). Loss of keratinocyte-restricted FAK, however, was associated with increased dermal proteolysis, presumably contributing to wound chronicity (Wong et al, 2014). In our previous study, inhibition of FAK with a small molecule inhibitor by local subcutaneous injection abrogated the local inflammatory responses and decreased scar development in a HTS mouse model (Wong et al, 2011a).…”

Section: Introductionmentioning

confidence: 86%

“…A key modulator of this process is focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase, which plays a central role in transducing mechanical signals to elicit fibrotic responses (Duscher et al, 2014;Wong et al, 2011aWong et al, , 2014. The integrin-FAK pathway also mediates tumor progression and metastasis in various malignancies (Guo et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation

Kwon

Padmanabhan

et al. 2018

Journal of Investigative Dermatology

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Formation of scars after wounding or trauma represents a significant health care burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, because of the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries. To address this issue, we have developed a pullulan collagen-based hydrogel to deliver FAKI to excisional and burn wounds in mice. Specifically, two distinct drug-laden hydrogels were developed for rapid or sustained release of FAKI for treatment of burn wounds and excisional wounds, respectively. Controlled delivery of FAKI via pullulan collagen hydrogels accelerated wound healing and reduced collagen deposition and activation of scar-forming myofibroblasts in both wound healing models. Our study highlights a biomaterial-based drug delivery approach for wound and scar management that has significant translational implications.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation

Kwon

Padmanabhan

et al. 2018

Journal of Investigative Dermatology

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“…UVR consistently induces MMP expression, in particular MMP-1 (corresponding to MMP-13 in mice) and MMP-9, in human and murine skin (29)(30)(31). Excessive MMP-1 and MMP-9 interfere with the necessary cell-matrix interactions during keratinocyte migration and specifically impairs epithelialization in murine wound healing models (32)(33)(34). The gap junction protein connexin-43 is upregulated by UVR (35) and overexpression of Wound contraction and incisional wound breaking strength were not influenced by UVR.…”

Section: Discussionmentioning

confidence: 99%

Acute Ultraviolet Radiation Perturbs Epithelialization but not the Biomechanical Strength of Full‐thickness Cutaneous Wounds

Danielsen

Lerche

Wulf

et al. 2016

Photochem & Photobiology

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We hypothesized that priming of the skin with ultraviolet radiation (UVR) before being injured would enhance wound healing. Four groups, each comprising 20 immunocompetent hairless mice, were exposed to simulated solar irradiation in escalating UVR doses; 0 standard erythema dose (SED) = control, 1 SED, 3 SED and 5 SED. Twenty-four hours after UV irradiation, inflammation was quantified by skin reflectance (erythema) and myeloperoxidase (MPO) tissue levels, and two 6 mm full-thickness excisional wounds and one 3 cm incisional wound were inflicted. Epidermal hyperplasia was assessed by quantitative histology. Five days after wounding, wound coverage by neoepithelium and wound width of the excisional wounds was quantified in hematoxylin-eosin sections, and breaking strength was measured in strips from incisional wounds. Erythema (P < 0.001), MPO levels (P < 0.0005) and epidermal cell layers (P < 0.001) increased dose-dependently by UV exposure of dorsal skin. In the excisional wounds, epithelial coverage decreased (P = 0.024) by increasing the UVR dose, whereas there was no significant difference (P = 0.765) in wound MPO levels. Neither wound width (P = 0.850) nor breaking strength (P = 0.320) differed among the groups. Solar-simulated UVR 24 h before wounding impaired epithelialization but was not detrimental for surgical incisional wound healing.

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“…Paradoxically, deletion of FAK signaling in keratinocytes had a different phenotype with atrophic dermis, indicating the complexity of epithelial-to-mesenchymal signaling that occurs during wound healing. 80 However, it is important to note that the significant differences between properties of mouse skin and those of human skin may limit our ability to translate these findings clinically. 81 Large animal studies have been conducted in the pig, which possesses skin similar to that of humans.…”

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confidence: 99%

Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation

Barnes

Marshall

Leavitt

et al. 2018

Advances in Wound Care

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171

131

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Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the wound environment enable us to target mechanical forces to minimize scar formation. Fetal wounds experience much lower resting stress when compared with adult wounds, and they heal without scars. Therapies that modulate mechanical forces in the wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless-type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance adult wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed.

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Loss of Keratinocyte Focal Adhesion Kinase Stimulates Dermal Proteolysis Through Upregulation of MMP9 in Wound Healing

Abstract: Keratinocyte FAK is highly responsive to mechanical cues and may play a critical role in matrix remodeling via regulation of p38 and MMP9. These findings suggest that aberrant epithelial mechanosensory pathways may contribute to pathologic dermal proteolysis and wound chronicity.

Cited by 36 publications

References 57 publications

Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation

Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation

Acute Ultraviolet Radiation Perturbs Epithelialization but not the Biomechanical Strength of Full‐thickness Cutaneous Wounds

Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation

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