Increased inflammation delays wound healing in mice deficient in collagenase‐2 (MMP‐8)

Abstract

Matrix metalloproteinases (MMPs) have been implicated in numerous tissue-remodeling processes. The finding that mice deficient in collagenase-2 (MMP-8) are more susceptible to develop skin cancer, prompted us to investigate the role of this protease in cutaneous wound healing. We have observed a significant delay in wound closure in MMP8-/- mice and an altered inflammatory response in their wounds, with a delay of neutrophil infiltration during the first days and a persistent inflammation at later time points. These changes were accompanied by alterations in the TGF-beta1 signaling pathway and by an apoptosis defect in MMP8-/- mice. The delay in wound healing observed in MMP8-/- mice was rescued by bone marrow transplantation from wild-type mice. Analysis of other MMPs showed that MMP8-/- mice had a significant increase in the expression of MMP-9, suggesting that both proteases might act coordinately in this process. This possibility was further supported by the novel finding that MMP-8 and MMP-9 form specific complexes in vivo. Taken together, these data indicate that MMP-8 participates in wound repair by contributing to the resolution of inflammation and open the possibility to develop new strategies for treating wound healing defects.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…Mice lacking MMP-8 show a delayed wound healing due to a persistent inflammatory infiltrates (see Table 6). Additionally, a decrease of collagen deposition has been observed in the wounds of these animals (Gutierrez-Fernandez et al, 2007). These studies indicate that MMP-8 can influence neutrophil recruitment during an acute inflammatory response, but at the same time it can help to resolve the inflammation at a later stage, as shown by the sustained number of neutrophils in MMP-8 deficient animals during the course of a chronic inflammation.…”

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

“…We have shown that MMP-9 is protective against VILI, whereas others have described beneficial effects of inhibition in different models of inflammation (14,25). To cite another example, lack of MMP-8 is protective in a model of acute liver injury (46) but can delay the resolution of inflammation in skin and lungs (3,20). These examples illustrate how nonselective inhibitors of MMPs can induce opposite effects, thus decreasing the probability of showing some clinical benefit.…”

The Collagen Binding Domain of Gelatinase A Modulates Degradation of Collagen IV by Gelatinase B

“…[47][48][49] Therefore, functional modulation of MMP9 enzymatic activity is of crucial importance for better comprehension of several pathological events. Previous findings sup- port the possibility that MMP8 and MMP9 form specific complexes in vivo, 50 suggesting that the two MMPs actually cooperate. Furthermore, other investigators pointed out that, depending on the specific context, gelatinases could work either in concert or antagonistically.…”