MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in mouse skin wound healing.
Matrix metalloproteinases (MMPs) have been implicated in wound healing. 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. Macroscopic wound closure was delayed in all of the KO mice, as compared with wild-type mice. The rate of re-epithelialization was significantly delayed in MMP-9 KO and MMP-13 KO mice and remarkably delayed in MMP-9/13 double KO mice, as compared with wild-type mice. Both MMP-9 and MMP-13 were expressed by the leading edges of epidermal cells in wild-type mice, and the migration of keratinocytes was suppressed by treatment with an MMP inhibitor or transfection of small interfering RNAs for MMP-9 or MMP-13, as compared with controls. The vascular density in wound granulation was significantly lower in both MMP-13 KO and MMP-9/13 double KO mice than in wild-type mice. Degradation of connective tissue growth factor in wound tissue was transiently prevented in MMP-13 KO mice. Morphometric analyses demonstrated a reduction in both wound contraction and myofibroblast formation in both MMP-13 KO and MMP-9/13 double KO mice. Proliferation and transforming growth factor-beta1-induced myofibroblast differentiation of dermal fibroblasts from MMP-13 KO mice were decreased, as compared with wild-type dermal fibroblasts. These data suggest that MMP-13 plays a role in keratinocyte migration, angiogenesis, and contraction in wound healing, while MMP-9 functions in keratinocyte migration.
Hattori
Noriko
N
Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.
Mochizuki
Satsuki
S
Kishi
Kazuo
K
Nakajima
Tatsuo
T
Takaishi
Hironari
H
D'Armiento
Jeanine
J
Okada
Yasunori
Y
D000818:Animals; D002465:Cell Movement; D015603:Keratinocytes / Q000201:enzymology / Q000502:physiology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D012867:Skin / Q000166:cytology / Q000293:injuries*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020780:Matrix Metalloproteinase 9