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Published as doi: 10.1096/fj.06-7860com.
 (The FASEB Journal. 2007;21:2580-2591.)
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Increased inflammation delays wound healing in mice deficient in collagenase-2 (MMP-8)

Ana Gutiérrez-Fernández*, Masaki Inada||, Milagros Balbín{ddagger}, Antonio Fueyo{dagger}, Ana S. Pitiot{ddagger}, Aurora Astudillo§, Kenji Hirose||, Michiko Hirata||, Steven D. Shapiro#, Agnès Noël**, Zena Werb{dagger}{dagger}, Stephen M. Krane{dagger}, Carlos López-Otín* and Xose S. Puente*,1

* Departamento de Bioquímica y Biología Molecular, and

{dagger} Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain;

{ddagger} Servicio de Oncología Molecular and

§ Anatomía Patológica, Hospital Central de Asturias, Oviedo, Spain;

|| Department of Medicine and

# Department of Medicine, Pulmonary and Critical Care, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, USA;

** Laboratory of Tumor and Development Biology, University of Liege, Liege, Belgium; and

{dagger}{dagger} Department of Anatomy, University of California, San Francisco, California, USA

1Correspondence: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain. E-mail: xspuente{at}uniovi.es

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-ß1 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.—Gutiérrez-Fernández, A., Inada, M., Balbín, M., Fueyo, A., Pitiot, A. S., Astudillo, A. Hirose, K., Hirata, M., Shapiro, S. D., Noël, A., Werb, Z., Krane, S. M. López-Otín, C., Puente, X. S.


Key Words: neutrophil • MMP-9 • cancer • protease • degradome




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