Increased inflammation delays wound healing in mice deficient in collagenase-2 (MMP-8).
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.
Gutiérrez-Fernández
Ana
A
Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, 33006 Oviedo, Spain.
Inada
Masaki
M
Balbín
Milagros
M
Fueyo
Antonio
A
Pitiot
Ana S
AS
Astudillo
Aurora
A
Hirose
Kenji
K
Hirata
Michiko
M
Shapiro
Steven D
SD
Noël
Agnès
A
Werb
Zena
Z
Krane
Stephen M
SM
López-Otín
Carlos
C
Puente
Xose S
XS
D000818:Animals; D016026:Bone Marrow Transplantation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D017403:In Situ Hybridization; D007249:Inflammation / Q000503:physiopathology*; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency* / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000235:genetics; D014945:Wound Healing / Q000502:physiology*
D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9