BASIC STUDY FOR THE TREATMENT OF SKIN DISEASES USING THE REGULATION OF MATRIX METALLOPROTEINASE-9 EXPRESSION

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Matrix metalloproteinase(MMP)-9 has been reported to play important roles in the tissue metabolism including the inflammation in many skin conditions. This project is designed because we have recently found the novel KRE-M9 element to which our designated differentiation repressing factor(DRF)-1 binds and because this mechanism is considered to be important for regulating MMP-9 expression.1.RNAi analyses for the DRF-1 and for the MMP-9,and the effects of decoy oligonucleotides for the KRE-M9 element-Using HT1080 cells and human primary kertinocytes in culture, RNAi for MMP-9 had the effects for inhibiting apoptosis. On the other hand, RNAi for DRF-1 had the inverse effects for apoptosis. In addition, the decoy ologoncleotides for KRE-M9 induced the cells to promote the MMP-9 expression together with apoptosis.2.Quest for the inhibitory molecules to MMP-9 expression and the appplication for disease models-Leptomycin B, which regulates nucleo-cytoplasmic trafficking of not a few proteins including transcription factor-related ones, showed the effects for upregulation not of MMP-2,but of MMP-9 expression by promoting its transcription for which KRE-M9 as well as the other elements is shown to be responsible. In addition, its topical application brought the UVB-irradiated skin of mouse the improvement of epidermal dyskeratosis together with the inflammatory infiltrates both in the dermis and in the subcutaneous fat tissue.3.Survey for MMP-9 expression in the skin conditions-1)The high levels of MMP-9 expresion were detected in the serum of the patient with toxic epidermal necrolysis. 2)Gelatinolytic activities were detected in the dyskeratotic lesions in squamous cell carcinoma. 3)Not only MMP-2,but also MMP-9 was detected from human fibroblasts in culture by the inflamatory cytokines.