Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing

Abstract

Keratinocyte growth factor (KGF) has been implicated in wound re-epithelialization and branching morphogenesis of several organs. To determine whether KGF induces these effects via induction of matrix metalloproteinase expression we have analysed the effect of KGF on the expression of stromelysin-2 in cultured HaCaT keratinocytes. Here we show a strong induction of stromelysin-2 mRNA within 5-8 h of stimulation of these cells with KGF. The degree of induction was similar to that achieved by treatment with epidermal growth factor or tumour necrosis factor alpha, whereas the stimulatory effect of transforming growth factor beta 1 was even stronger. To determine whether the induction of stromelysin-2 expression by growth factors and cytokines might be important for wound healing, we analysed the expression of this gene during the healing process of full-thickness excisional wounds in mice. Whereas stromelysin-2 mRNA could hardly be detected in unwounded skin, a biphasic induction was seen after injury and highest levels were found at days 1 and 5 after wounding. Hybridization in situ revealed the presence of stromelysin-2 mRNA in basal keratinocytes at the wound edge but not in the underlying mesenchymal tissue. During impaired wound healing as seen in glucocorticoid-treated mice, stromelysin-2 expression was significantly increased compared with untreated control mice. Taken together, these results suggest that correct regulation of this broad-spectrum metalloproteinase might be important for normal repair.

Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers

“…Instead, gelatinase A protein did not colocalize with laminin-5 and apparently does not cleave laminin-5 during skin carcinogenesis. Interestingly, TGF-β1 is able to induce both MMP-10 (Madlener et al, 1996) and laminin-5 in keratinocytes (Kainulainen et al, 1998). Cultured human foreskin keratinocytes express MMP-10, while fibroblasts express MMP-3.…”

“…Previous studies have shown, that the expression of MMP-10 is induced by phorbol ester, TGF-α and epidermal growth factor (EGF) in normal epidermal keratinocytes and by KGF, EGF, TNF-α and TGF-β1 in HaCaT keratinocytes (Madlener et al, 1996). 43 cell lines established from primary and recurrent tumours and metastases of SCCs of the head and neck at the time of operation in the Turku University Central Hospital (Johansson et al, 1997b) were examined for basal expression of MMP-10.…”

“…However, MMP-10 has an important role in cutaneous and intestinal wound healing. It is expressed at the wound edge by migrating basal keratinocytes during both human and murine wound repair (Saarialho-Kere et al, 1994;Madlener et al, 1996) and by migrating enterocytes in inflammatory bowel disease (Vaalamo et al, 1998).…”

Matrix Metalloproteinase 10 Degradomics in Keratinocytes and Epidermal Tissue Identifies Bioactive Substrates With Pleiotropic Functions*

“…MMP10-dependent processing of DMKN is of particular interest, because DMKN expression in skin wounds spatially and temporally overlaps with increased levels of MMP10 in wound edge keratinocytes (4,(73)(74)(75). Moreover, recombinant DMKN inhibited ERK phosphorylation in cultured keratinocytes and delayed wound closure in mice (75,76).…”

Novel roles of NM23 proteins in skin homeostasis, repair and disease

“…For these experiments, we used RNA isolated from quiescent and KGF-stimulated HaCaT keratinocytes. Genes identified so far encode, for example, nucleotide biosynthesis enzymes (Gassmann et al, 1999), which are required for proliferation, the estrogen-responsive B box protein (Beer et al, 2002), which initiates early differentiation, and stromelysin-2 (Madlener et al, 1996;Krampert et al, 2004), which regulates migration. Finally, the transcription factor Nrf2 (Braun et al, 2002;auf dem Keller et al, 2006) and the non-selenium glutathione peroxidase peroxiredoxin 6 (Frank et al, 1997) mediate protection of epithelial cells against cytotoxic agents such as reactive oxygen species.…”