Matrikines as mediators of tissue remodelling

Matrix-derived peptides may penetrate skin via multiple pathways to act on cutaneous cells. At the cellular level, the mechanisms of action of some elastin derived peptides are well known but the receptors and signalling mechanisms for other extracellular matrix peptides are yet to be established. In both panels solid lines and arrows represent known pathways, while dotted lines indicate gaps in our current understanding. Abbreviations: ERC, elastin receptor complex; Gal-3, galectin-3; ERK, extracellular signal-regulated kinase; AP-1, activator protein-1; MMP, matrix metalloproteinase; ECM, extracellular matrix. [Display omitted] Extracellular matrix (ECM) proteins confer biomechanical properties, maintain cell phenotype and mediate tissue repair (via release of sequestered cytokines and proteases). In contrast to intracellular proteomes, where proteins are monitored and replaced over short time periods, many ECM proteins function for years (decades in humans) without replacement. The longevity of abundant ECM proteins, such as collagen I and elastin, leaves them vulnerable to damage accumulation and their host organs prone to chronic, age-related diseases. However, ECM protein fragmentation can potentially produce peptide cytokines (matrikines) which may exacerbate and/or ameliorate age- and disease-related ECM remodelling. In this review, we discuss ECM composition, function and degradation and highlight examples of endogenous matrikines. We then critically and comprehensively analyse published studies of matrix-derived peptides used as topical skin treatments, before considering the potential for improvements in the discovery and delivery of novel matrix-derived peptides to skin and internal organs. From this, we conclude that while the translational impact of matrix-derived peptide therapeutics is evident, the mechanisms of action of these peptides are poorly defined. Further, well-designed, multimodal studies are required.