Role of Collagenase in Wound Healing

It is reasonable to assume, based on the research partly reviewed here, that collage-nase-1 has a key role in the wound healing process. Expression of collagenase in dermal cells, consistently found in repairing skin wounds seems more logical than the finding of collagenase in epithelial cells. Tissue repair involves the turnover of dermal fibrillar collagen, a process requiring the proteolytic activity of collagenases. Increased collagenolysis is needed throughout the remodeling phase leading to the formation of a mature scar, a process requiring months. During this period, there are marked changes in collagen composition, and the amount of type III collagen. Although transiently present in elevated levels in the early wound matrix, type III collagen expression decreases, and shifts towards the formation of type I collagen and the subsequent maturation of collagen into thicker and more compact fibers. Collagenases are obvious participants in this process and collagenase-1 seems to be the principal enzyme involved, although neutrophil collagenase released from migratory inflammatory cells may assist in collagen degradation. The potential role for collagenase 3 in this context is only beginning to be studied. Our own data do not show evidence of collagenase 3 expression in acute skin wounding (Stähle-Bäckdahl, unpublished observations). However, Saarialho-Kere recently showed that collagenase 3 was expressed by dermal fibroblasts in chronic wounds, suggesting that collagenase 3 may be involved in matrix remodeling associated with wounding.95

There is no doubt that the principal function of epidermal cells expressing collagenase is in closing the wound by cell migration and proliferation. What is the specific role for collagenase-1 in this setting, and is it critical for cell immigration? A hypothesis recently advanced is that collagenase activity is necessary for the keratinocyte to achieve re-epithe-lialization. In support of this idea Pilcher et al have shown that keratinocyte migration in vitro is dependant upon catalytically functional collagenase.63 As discussed earlier, it is well-established that keratinocytes migrating on type I collagen produce collagenase in vitro. Indeed, when blocking collagenase activity in this system, the keratinocytes failed to migrate. It was further hypothesized that keratinocyte migration would only occur in association with collagenase cleaving collagen molecules. Consistent with this, it was shown that the cells did not migrate on mutant collagen lacking the collagenase cleavage site, a finding strongly linking collagenase catalytic activity to keratinocyte movement. Thus, there is substantial evidence supporting a direct role for collagenase in keratinocyte migration. Moreover, in this model the authors proposed that by cleaving collagen fibers, collagenase actually serves to direct the keratinocytes during migration; the keratinocytes are provided fresh collagen substrate ahead and leave behind digested gelatin fragments no longer attracting collagenase. Admittedly, it is tempting to speculate that the critical role for collagenase in re-epithelialization utilizes its unique biological role. However, even though collagenase may be required for cell migration and epithelial regeneration, its precise functions in the wounded epidermis are more elusive. The assumption is that re-epithelialization in different tissues follows similar if not identical mechanisms. Consistent with this are experimental data on mucosal healing showing that analogous to the situation in skin, contact with type I collagen stimulates epithelial cell migration more than does contact with fibronectin and laminin. Therefore, it is somewhat surprising that healing of ulcers in the gastrointestinal mucosa does not seem to involve collagenase-1. In such lesions there is distinct expression of matrilysin (MMP-7) but not collagenase-1 in the wound edge epithelium, the latter detected only in the stromal tissue underneath. Matrilysin has a broad substrate specificity but it does not cleave type I collagen, indicating a different role in re-epithelialization that does not involve collagen.

Another interesting question concerns the role of type III collagen in this setting. Type III collagen is the preferred substrate for collagenase-1 in vitro and one might infer that collagenase-1 may have evolved to serve a unique role in tissues containing by a high collagen III content. In fresh wounds the deposition of granulation tissue occurs in an orderly sequence lead by fibronectin, followed by type III collagen, and then by type I collagen. This time course seems to match the appearance of collagenase-1 expression in wound edge keratinocytes and it is tempting to connect the two. Does type III collagen induce collage-nase-1 in migrating keratinocytes?

A clinically relevant issue concerns chronic skin ulcers. By their chronic nature, these ulcers have a problem in the process of healing. Despite overexpression of collagenase-1 in such wounds, at levels even more pronounced than in acute wounds,37 these ulcers do not re-epithelialize effectively. So, even though collagenase-1 may be required for re-epithelial-ization, it is not sufficient for keratinocyte migration to take place. Despite ample collage-nase-1 production, epithelial cells in chronic wounds lose their migratory phenotype and "forget" that they are wound edge keratinocytes. These keratinocytes can temporarily reassume a migratory phenotype if challenged by additional injury. In clinical practice, use is made of this empirical observation when performing surgical revision of a wound, which sometimes enhances re-epithelialization. What is the mysterious signal elicited by the injury that can stimulate the keratinocytes to migrate? One can speculate about the signals involved, but clearly it is not solely the upregulation of collagenase-1.

In summary, research over the past few years has shown us that collagenase-1 is a key component of skin wound healing. Besides participating in the remodeling of the wounded dermal tissue, collagenase-1 serves a distinct role in epithelial wound closure. Many questions remain, but additional insight into the mechanisms of keratinocyte migration will provide us with powerful tools to effectively intervene in and facilitate the wound healing process.

Acknowledgements

The Karolinska Institute and the Welander-Finsen Foundation are gratefully acknowledged for financial support and the Journal for Investigative Dermatology for the use of figures published in the journal 104:479-483, 1995.

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