Matrix metalloproteinase-19 expression in dermal wounds and by fibroblasts in culture.
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-alpha (TNF-alpha). Induction of MMP-19 expression by TNF-alpha 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 (NK). 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.
Hieta
Niina
N
Centre for Biotechnology, University of Turku and Abo Akademi University, Turku, Finland.
Impola
Ulla
U
López-Otín
Carlos
C
Saarialho-Kere
Ulpu
U
Kähäri
Veli-Matti
VM
D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology; D005347:Fibroblasts / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases / Q000032:analysis / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014945:Wound Healing; D014947:Wounds and Injuries / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053505:Matrix Metalloproteinases, Secreted; D008666:Metalloendopeptidases; C108362:matrix metalloproteinase 19