The extra-cellular matrix (ECM) is a source of biochemical and biomechanical influences that direct cell proliferation and fate. However, the molecular mechanisms underlying the interplay between these influences and tissue homeostasis, while still relatively ill-defined, are thought to be controlled by a suite of mechano-transduction pathways. The ROCK signalling pathway lies at the interface between mechanical and biochemical signalling and is well known to regulate the structure and contractility of the actomyosin cytoskeleton. However, we have shown that ROCK signalling also promotes epidermal proliferation and wound healing by co-opting a paracrine signalling mechanism that increases ECM production and impairs ECM remodelling, thereby elevating dermal stiffness and enhancing integrin-mediated mitogenic pathways.
Signal flux through the ROCK pathway is moderated by a member of the 14-3-3 family of adaptor proteins and molecular chaperones, 14-3-3ζ. Impairing 14-3-3ζ function either by genetic ablation or pharmacological inhibition accelerated wound healing by enhancing ROCK signalling. Interestingly, enhancement of wound healing was also observed in the slow-healing wounds of diabetic mice when treated with 14-3-3ζ inhibitor. A significant proportion of chronic non-healing wounds in patient samples exhibited increased expression of 14-3-3ζ as observed by quantitative immunofluorescence analysis. Taken together our observations suggest that pharmacological inhibition of 14-3-3ζ may benefit patients whose chronic non-healing wounds are characterised by increased expression of 14-3-3ζ.