Impaired Wound Contraction in Stromelysin-1–Deficient Mice

Perturbation of the balance between extracellular matrix (ECM) degradation and deposition contributes to a number of pathologic conditions characterized by abnormal healing and chronic inflammation. 1–3 Matrix metalloproteinases are expressed in migrating keratinocytes, the adjacent dermis, and granulation tissue of healing wounds, and their altered functions have been implicated in disease processes characterized by abnormal healing. 4–7 Stromelysin-1 (matrix metalloproteinase-3) degrades proteoglycans, laminin, fibronectin, the nonhelical domains of collagen types IV and IX, propeptides of type I collagen, and denatured collagens and activates collagenase-1. 8–11 It is synthesized primarily by fibroblasts and to a lesser extent by activated macrophages and keratinocytes adjacent to sites of injury. 12–14 Stromelysin-1 is found in settings where active ECM remodeling occurs, including the stroma of normally healing rabbit corneal wounds, 7 stromal cells and keratinocytes of chronic ulcers, 14 and burn wound fluid from humans. 15 With the possible exception of interstitial collagenase, metalloproteinase activities are overlapping. Compensatory mechanisms have been observed in stromelysin-1–deficient (Str-1-/-) mice in studies of uterine involution 16 and collagen-induced arthritis. 17 We designed a study to investigate the impact of disruption of the stromelysin-1 gene on incisional and excisional dermal wound healing in mice. In contrast to previous studies on mice with a disrupted stromelysin-1 gene, 16,17 this study describes a phenotype in Str-1-/- mice that is not compensated by other metalloproteinases. Our results demonstrate that under the stress of excisional wound repair, deletion of stromelysin-1 results in a failure of wound contraction and significantly delayed healing.