MMP generated matrikines

Abstract

Matrikines originate from the fragmentation of extracellular matrix proteins and regulate cellular activities by interacting with specific receptors. Matrikines are implicated in inflammation, immune responses, organ development, wound repair, angiogenesis, atherosclerosis, tumor progression and metastasis due to their ability to alter cellular migration, chemotaxis, and mitogenesis. Matrix metalloproteinases (MMPs) degrade extracellular matrix components under normal circumstances and in disease processes. Of the 20 MMPs identified, MMP-1, MMP-2, MMP-8, MMP-9, and MMP-12 have been implicated in regulating the matrikines val-gly-val-ala-pro-gly (elastin peptide) and proline-glycine-proline (PGP). Elastin peptide fragments are generated from elastolytic enzymes and have implications in atherosclerosis, neovascularization, chronic obstructive pulmonary disease, skin disease, as well as tumor invasion and spread. PGP is produced through a multistep pathway that liberates the tripeptide fragment from extracellular collagen. PGP is best described for its role in neutrophil chemotaxis and is implicated in the pathogenesis of corneal ulcers and in chronic lung conditions. In chronic cigarette smoke related lung disease, the PGP pathway can become a self-propagating cycle of inflammation through cigarette-smoke mediated inhibition of leukotriene A4 hydrolase, the enzyme responsible for degrading PGP and halting acute inflammation. This review highlights the roles of MMPs in generating these important matrikines.

The extracellular matrix in myocardial injury, repair, and remodeling

“…In injured and remodeling tissues, protease-mediated fragmentation of matrix proteins results in generation of matrikines (29)(30)(31)(32). Elastin fragments and collagen-derived peptides are the best-studied matrikines and have been implicated in activation of immune cells and fibroblasts (29,33).…”

“…In injured and remodeling tissues, protease-mediated fragmentation of matrix proteins results in generation of matrikines (29)(30)(31)(32). Elastin fragments and collagen-derived peptides are the best-studied matrikines and have been implicated in activation of immune cells and fibroblasts (29,33). The collagen-derived tripeptide proline-glycine-proline (PGP) and its acetylated form have been demonstrated as acting as neutrophil chemoattractants in models of pulmonary inflammation, signaling through activation of the chemokine receptor CXCR2 (34).…”

Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium

“…Indeed, ECM structure and composition provides a 512 scaffold and signals for cell adhesion and migration during tissue restoration [Li et al, 2005]. 513 ECM effect on angiogenesis appears highly variable over time, strictly depending on protein 514 constituents, protease actions, and ECM ability to sequester growth factors and bioactive 515 molecular fragments [Wells et al, 2015]. Significantly, MMP-mediated degradation of ECM 516 can promote endothelial cell migration through exposure of pro-migratory matrix molecule 517 binding sites [Pepper, 2001;Hangai et al, 2002].…”

“…Furthermore, pro-inflammatory cytokines strongly induce the production of matrix 112 metalloproteinases (MMPs) and down-regulate the levels of tissue inhibitors of 113 metalloproteinases (TIMPs), thereby creating an environment with unbalanced MMP/TIMP 114 ratios [Diegelmann et al, 2004;Pepper, 2001]. Consequently, wound repair mediators 115 become targets of proteases, and the resultant matrix degradation contributes to the delay in 116 re-epithelialization, fibroplasia and angiogenesis [Pepper, 2001;Wells et al, 2015]. 117…”

Endorepellin-evoked Autophagy Contributes to Angiostasis

“…Endorepellin is found in vivo, where it is proteolytically processed from perlecan (14) via matrix metalloproteinases, a family of enzymes involved in a multitude of biological processes (35)(36)(37)(38)(39). Although perlecan mRNA can undergo alternative splicing, no evidence exists for endorepellin production in vivo via this mechanism (14).…”