COLLAGENASE-3 (MATRIX METALLOPROTEINASE-13) GENE-EXPRESSION BY HACAT KERATINOCYTES IS ENHANCED BY TUMOR-NECROSIS-FACTOR-ALPHA AND TRANSFORMING GROWTH-FACTOR-BETA

Collagenase-3 (matrix metalloproteinase 13; MMP-13) is a novel matrix metalloproteinase, the expression of which to date has only been detec ted in human breast carcinoma tissue and osteoarthritic cartilage. Her e, we show that MMP-13 transcripts are expressed by human HaCaT kerati nocytes but not by primary human epidermal keratinocytes. The levels o f MMP-13 mRNAs in HaCaT cells were enhanced up to 130- and 45-fold by tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta), respectively, The maximal induction of MMP-13 mRNAs by TNF-alpha was noted after a 6-h incubation, whereas with TGF-beta, the maximal stimulation was observed after 24 h. The up-regulation of MMP-13 mRNA abundance by TNF-alpha and TGF-beta was dependent on prote in synthesis and was prevented partially by dexamethasone and retinoic acid, Nuclear run-on assays demonstrated activation of MMP-13 gene tr anscription by TNF-alpha maximally at the 2-h time point and by TGF-be ta after 12 h of treatment, Incubation of HaCaT keratinocytes with TNF -alpha and TGF-beta also increased production of proMMP-13 into the cu lture media, as detected by Western blotting, Our data indicate that t he MMP-13 gene is expressed by transformed epidermal keratinocytes, su ggesting a role for MMP-13 in the invasive capacity of human epidermal malignancies.