In this study, we examined the impact of
matrix metalloproteinases (
MMP) on epithelialization, granulation tissue development,
wound contraction, and alpha-smooth muscle actin (
ASMA) expression during cutaneous
wound repair through systemic administration of the synthetic broad-spectrum
MMP inhibitor GM 6001 (N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-
L-tryptophan methylamide). Four full-thickness excisional
wounds (50 mm2) on the back of 22 young female Sprague-Dawley rats, 12 treated with
GM 6001 100 mg/kg and 10 with vehicle, were allowed to heal by secondary intention. GM 6001-treated
wounds were minimally resurfaced with neoepithelium, despite unaltered keratinocyte proliferation in
wound edges, whereas control
wounds were completely covered with 3-7 cell layers of parakeratinized epithelium on post-wounding day 7.
Hydroxyproline concentration, a marker of
collagen, and cell proliferation in granulation tissue did not differ significantly between GM 6001-treated and control groups. Impaired
wound contraction (P < 0.01) was associated with a dramatic reduction of
ASMA-positive myofibroblasts in granulation tissue of
GM 6001 wounds. This was not due to
GM6001 blocking
transforming growth factor-beta1 (TGF-beta1)-induced myofibroblast differentiation since
GM 6001 did not inhibit TGF-beta1-induced
ASMA expression and force generation in cultured rat dermal fibroblasts. The profound impairment of skin repair by the nonselective
MMP inhibitor GM 6001 suggests that keratinocyte resurfacing,
wound contraction, and granulation tissue organization are highly
MMP-dependent processes.