Proteolytic Events of Wound-Healing — Coordinated Interactions Among Matrix Metalloproteinases (MMPs), Integrins, and Extracellular Matrix Molecules

Abstract

During wound-healing, cells are required to migrate rapidly into the wound site via a proteolytically generated pathway in the provisional matrix, to produce new extracellular matrix, and, subsequently, to remodel the newly formed tissue matrix during the maturation phase. Two classes of molecules cooperate closely to achieve this goal, namely, the matrix adhesion and signaling receptors, the integrins, and matrix-degrading and -processing enzymes, the matrix metalloproteinases (MMPs). There is now substantial experimental evidence that blocking key molecules of either group will prevent or seriously delay wound-healing. It has been known for some time now that cell adhesion by means of the integrins regulates the expression of MMPs. In addition, certain MMPs can bind to integrins or other receptors on the cell surface involved in enzyme activation, thereby providing a mechanism for localized matrix degradation. By proteolytically modifying the existing matrix molecules, the MMPs can then induce changes in cell behavior and function from a state of rest to migration. During wound repair, the expression of integrins and MMPs is simultaneously up-regulated. This review will focus on those aspects of the extensive knowledge of fibroblast and keratinocyte MMPs and integrins in biological processes that relate to wound-healing.

Annexin I Regulates SKCO-15 Cell Invasion by Signaling through Formyl Peptide Receptors

“…The classic bacterial derived FPR-1 ligand, fMLP, has also been shown to activate FPRL-1, albeit with significantly reduced affinity (79). Other infectious agent-derived agonists include human immunodeficiency virus, type 1 envelope proteins and the Helicobacter pylori peptide Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). WKYMVm is an agonist for all three nFPR family members that were derived from peptide libraries (80,81).…”

Integrin Regulation of Epidermal Functions in Wounds

“…While the effects of local matrix remodeling on epidermal functions are clear, longrange effects of altered wound ECM are also important. Indeed, controlled ECM remodeling is an essential feature of normal wound healing, 138 and defects in ECM organization are associated with chronic wounds. 139 It has long been known that changes in matrix composition or structure can act upstream of integrins through ligation that turns on intracellular signaling pathways.…”

Dermal Transforming Growth Factor-β Responsiveness Mediates Wound Contraction and Epithelial Closure

“…Integrins are transmembrane proteins that form ␣␤ heterodimers and act as receptors for extracellular matrix proteins. 34 Integrins are also critical in keratinocyte adhesion and migration, 34 and they are the principal means of transducing forces and signals between the cytoplasm and the extracellular matrix in mesenchymal cells by linking the extracellular environment to the actin cytoskeleton via connections with adaptor proteins such as talin and filamin. 35 The expression of ␣1 integrin, ␣2 integrin, and ␤1 integrin, which constitute the principal collagen receptors, was significantly decreasedϩ in Tgfbr2 dermalKO fibroblasts compared with control by 3.5-fold (P Ͻ 0.001), 2.1-fold (P Ͻ 0.001), and 2.1-fold (P Ͻ 0.001), respectively ( Figure 5C).…”