Matrix Metalloproteinases, Gelatinase and Collagenase, in Chronic Leg Ulcers

Abstract

Although extracellular proteolysis is a prerequisite for normal wound healing, uncontrolled proteolytic tissue destruction appears to be a pathogenic factor in non-healing wounds. The aim of our study was to compare the activities of the serine proteinases of polymorphonuclear origin, elastase and cathepsin G, and the metalloproteinases, gelatinase and collagenase, in chronic leg ulcer exudate (10 patients) and acute wound fluid (6 patients). Serine proteinase activities were low in leg ulcer exudates but very high in some but not all acute wound fluids. Total collagenase activity, measured as activity against type I collagen monitored by SDS-PAGE and densitometry, was higher in chronic leg ulcer exudate than in acute wound fluid and its degree of autoactivation was relatively high. Doxycycline inhibition studies suggested that the collagenase activity in chronic leg ulcer exudate was MMP-1 ("fibroblast-type") and not MMP-8 ("neutrophil-type"). Zymographic analysis of the gelatinolytic enzymes in acute wound fluid showed a progressive increase from the day of operation to postoperative day 5, but the degree of activity was lower than in chronic leg ulcer exudate and the low molecular mass activation products were faint. The leg ulcer gelatinase profiles were characterized by high expression of 92/82- and 72/62-kDa duplex bands and by the presence of low molecular mass activation products. Leg ulcer collagenase seems to be derived from mononuclear rather than polymorphonuclear cells, which are known to be involved in acute wound healing. In conclusion, the present study shows that gelatinase and collagenase, but not elastase and cathepsin G are found in chronic leg ulcer exudate.

Androgens influence expression of matrix proteins and proteolytic factors during cutaneous wound healing

“…In chronic, non-healing wounds, these processes are disturbed and excessive tissue breakdown results in the failure to accumulate sufficient amounts of several key matrix components as a result of both decreased rates of protein biosynthesis 33 and greatly increased proteolytic activity. 34 Intriguingly, male gender is the primary factor predisposing to chronic wound healing states in humans, 23 and our recent studies have demonstrated that androgens impair healing in mouse and human models. 19 Previous studies have suggested that androgens may stimulate collagen production: DHT was shown to drive cutaneous expression of the gene encoding pro-a1 (I) collagen 35 and dermal collagen content was reported to be increased in elderly women receiving androgen treatment for osteoporosis.…”

Recombinant AAV vector encoding human VEGF165 enhances wound healing

“…Growth factors might be trapped within extracellular matrix molecules, 14 or degraded by increased protease activity found in chronic non-healing wounds. 15 Alternatively, growth factor production might be impaired at the gene expression level, as we have recently observed for VEGF in the genetically diabetic mouse. 16 Given these considerations, it stems evident that a reasonable approach to alter the microenvironment of the wounded tissue and to stimulate wound healing is the topical application of growth factors.…”

RETRACTED: Gene therapy and wound healing

“…As outlined above, a major pathogenic factor of the chronic non-healing wound environment is a high level of wound proteases (24)(25)(26)(27)29,30). Administration of recombinant TIMP-2, a metalloproteinase inhibitor, promoted tissue repair in a rat model (128).…”

“…There is increasing evidence that the persisting infiltration of neutrophils and macrophages plays a major role in the generation of a protease rich and prooxidant hostile microenvironment (21)(22)(23). Recent experimental and several comprehensive clinical studies demonstrated that the proteolytic activity of matrix metalloproteinases and serine proteinases is significantly upregulated in the exudate of chronic wounds (24)(25)(26)(27), thus contributing to the degradation of extracellular matrix molecules (24,25), growth factors and their receptors (28)(29)(30). In addition, proteolytic degradation products generated by high protease activity in the chronic wound environment may exert inhibitory effects on cell function (31).…”