1. ^*Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland
2. ^†Department of Dermatology, University of Turku, Turku, Finland
3. Department of Medical Biochemistry, University of Turku, Turku, Finland
4. ^§Departamento Bioquimica y BiologÌa Molecular, Instituto Universitario de Oncologia, Universidad de Oviedo, Oviedo, Spain
5. ^‡Department of Dermatology, University of Helsinki and Biomedicum Helsinki, Helsinki

Correspondence: Veli-Matti Kahari, MD, PhD, Center for Biotechnology, University of Turku, Tykistökatu 6B, FIN-20520 Turku, Finland. Email: veli-matti.kahari@utu.fi

Received 11 December 2002; Revised 14 March 2003; Accepted 6 May 2003; Published online 31 October 2003.

Abstract

Here, we have examined the expression of matrix metalloproteinase-19 (MMP-19) in human cutaneous wounds and by human skin fibroblasts in culture. Expression of MMP-19 was detected by immunohistochemistry in fibroblasts, capillary endothelial cells, and macrophages in the dermal layer of large granulating wounds, as well as in chronic venous and decubitus ulcers. MMP-19 mRNA expression and pro-MMP-19 production by dermal fibroblasts in culture was potently enhanced by tumor necrosis factor- (TNF-). Induction of MMP-19 expression by TNF- was prevented partially by blocking the activation of extracellular signal-regulated kinase (ERK)-1/2 by PD98059 and p38 activity by SB203580. Activation of ERK1/2 by adenovirus-mediated delivery of constitutively active MAPK/ERK kinase 1 resulted in the induction of MMP-19 expression. Activation of p38 alone by adenovirally delivered constitutively active MAPK kinase 3b (MKK3b) and MKK6b also enhanced MMP-19 production, and the most potent induction of MMP-19 expression was noted when ERK1/2 was activated in combination with p38. Activation of c-Jun N-terminal kinase (JNK). Abundant pro-MMP-19 production by fibroblasts was associated with proteolytic processing of secreted pro-MMP-19. These results suggest a role of MMP-19 in cutaneous wound repair and identify three distinct signaling pathways, which coordinately mediate induction of MMP-19 expression in fibroblasts: mitogen-activated ERK1/2 pathway and stress-activated JNK and p38 pathways, of which control proteolytic activity of dermal fibroblasts.