MMP-13 Plays a Role in Keratinocyte Migration, Angiogenesis, and Contraction in Mouse Skin Wound Healing

Noriko Hattori^*, Satsuki Mochizuki^*, Kazuo Kishi, Tatsuo Nakajima, Hironari Takaishi, Jeanine D'Armiento and Yasunori Okada^*

Departments of Pathology,^* Plastic Surgery, and Orthopediac Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan; and the Department of Molecular Medicine, Columbia University, College of Physicians and Surgeons, New York, New York

Matrix metalloproteinases (MMPs) have been implicated in woundhealing. To analyze the roles of MMP-9 and MMP-13 in wound healing,we generated full-thickness cutaneous wounds in MMP-9 knockout(KO), MMP-13 KO, MMP-9/13 double KO, and wild-type mice. Macroscopicwound closure was delayed in all of the KO mice, as comparedwith wild-type mice. The rate of re-epithelialization was significantlydelayed in MMP-9 KO and MMP-13 KO mice and remarkably delayedin MMP-9/13 double KO mice, as compared with wild-type mice.Both MMP-9 and MMP-13 were expressed by the leading edges ofepidermal cells in wild-type mice, and the migration of keratinocyteswas suppressed by treatment with an MMP inhibitor or transfectionof small interfering RNAs for MMP-9 or MMP-13, as compared withcontrols. The vascular density in wound granulation was significantlylower in both MMP-13 KO and MMP-9/13 double KO mice than inwild-type mice. Degradation of connective tissue growth factorin wound tissue was transiently prevented in MMP-13 KO mice.Morphometric analyses demonstrated a reduction in both woundcontraction and myofibroblast formation in both MMP-13 KO andMMP-9/13 double KO mice. Proliferation and transforming growthfactor-β1-induced myofibroblast differentiation of dermalfibroblasts from MMP-13 KO mice were decreased, as comparedwith wild-type dermal fibroblasts. These data suggest that MMP-13plays a role in keratinocyte migration, angiogenesis, and contractionin wound healing, while MMP-9 functions in keratinocyte migration.