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

• DOI: 10.1096/fj.06-7860com
• Publication Date: 2007-03-29T01:03:45Z
• Authors: Ana Gutiérrez-Fer...; Masaki Inada; Milagros Balbín; Antonio Fueyo; Ana S. Pitiot; Aurora Astudillo; Kenji Hirose; Michiko Hirata; Steven D. Shapiro; Agnès Noël; Zena Werb; Stephen M. Krane; Carlos López-Otín; Xose S. Puente
• Keywords: Inflammation; Mice, Knockout; 0301 basic medicine; Wound Healing; Skin Neoplasms; 3. Good health; Mice; 03 medical and health sciences; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Animals; Genetic Predisposition to Disease; In Situ Hybridization; Bone Marrow Transplantation

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.