The Role Of MMPs In Chronic Wound Edema
Wound healing progresses through a series of processes, which include the formation of granulation tissue, epithelialization and connective tissue remodeling. These events require continuous modification of the complex cellular support matrix. This matrix is comprised of: structural proteins (collagen and elastin); specialized “anchoring” proteins (fibronectin, laminin and fibrillin); and proteoglycans and glycosaminoglycans (GAGs) such as hyaluronic acid, chondroitin sulfate, heparan sulfate, heparin, dermatan sulfate and keratan sulfate. Blood vessels that deliver oxygen and nutrients to the extracellular matrix (ECM) also undergo modification.
Matrix metalloproteinases (MMPs) are neutral endopeptidases. These enzymes modify the ECM in support of wound healing, morphogenesis, tissue resorption and remodelling, nerve growth and hair follicle development. MMPs direct wound healing by controlling platelet aggregation, macrophage and neutrophil function, cell migration and proliferation, angiogenesis and collagen secretion.
MMPs exert their effect by modulating enzyme cascades and by either activating or inactivating matrix proteins, cytokines, growth factors and adhesion molecules. Pathologic MMP expression has been implicated in a variety of disease processes such as chronic wound ulceration, rheumatoid arthritis, osteoarthritis, cancer invasion, cancer metastasis, periodontal diseases, fibrotic diseases, atherosclerosis, epidermolysis bullosa and aortic aneurysm.
MMPs are a gene family that contains zinc2+-binding domain in their active sites and calcium ions to maintain structure. Enzymes are divided into subfamilies of secretory enzymes (collagenases, gelatinases, stromelysins, unclassified) and membrane-bound type enzymes (MT-MMPs) based upon structural characteristics and the substrates they preferentially bind. During normal skin repair, keratinocytes, fibroblasts, macrophages and endothelial cells secrete MMPs and express MT-MMPs on their surfaces.
Multiple factors dictate the type and amount of MMP expression. These factors include available cytokines, growth factors, hormones, oncogenes, changes in cell-cell interactions, cell-matrix interactions as well as feedback from inflammatory mediators. Tumor necrosis factor (TNF), interleukin-1, interleukin-6 and interleukin-8 have been shown to have specific MMP links.
How Do MMPs Make An Impact On Wound Healing?
MMPs exert their effect through several modes of action.
• They change cell adherence to gel, which influences cell migration.
• They promote cellular proliferation apoptosis or morphogenesis, and can dictate the number and type of cellular concentration in the tissue.
• They modulate biological active molecules, such as growth factors (GF) and growth factor receptors (GFR).
MMP proteolytic activity is controlled by three mechanisms:
• regulation of the transcription process;
• enzymes are transcribed as zymogens; and
• interaction with specific tissue inhibitory matrix proteins (TIMPs).
MMPs are synthesized as pre-proenzymes and subsequently bound to the cell surface or secreted into the extracellular space. Interaction of a cysteine amino acid residue with the zinc2+ moiety at the catalytic site maintains the enzyme in a latent state. Zinc2+ has four binding sites and the cysteine-zinc bond produces a fold that conceals the catalytic site. Disruption of the bond exposes the catalytic site and expresses the “active” state. This process is called the cysteine switch. TIMP –1, -2, -3 and –4 inhibit MMP activity by inserting their terminal amino acid residue into the fourth zinc2+ site.
Additionally, medicines are used to inhibit MMPs. Macrolide antibiotics (erythromycin, azithromycin, tetracycline) have been shown to retard tissue breakdown independent of their antibiotic effect. More than thirteen new macrolide-based MMP inhibitors are under investigation. Moreover, some nonsteroidal antiinflammatory drugs (NSAIDs) inhibit MMP activity with transcription repression as the proposed mechanism.