LIPODERMATOSCLEROSIS IS CHARACTERIZED BY ELEVATED EXPRESSION AND ACTIVATION OF MATRIX METALLOPROTEINASES - IMPLICATIONS FOR VENOUS ULCER FORMATION

Lipodermatosclerosis refers to skin induration of the lower extremitie s and is associated with patients preceding venous ulcerations. To bet ter understand the pathogenesis of ulcer formation we investigated the expression of matrix metalloproteinases (MMP) and tissue inhibitors o f metalloproteinases (TIMP) in lipodermatosclerosis. By preparing biop sies from healthy skin and liposclerotic lesions, MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were analyzed by using reverse transcriptase-polym erase chain reaction, western blot, zymography, hydrolysis of [H-3]lab eled collagens, and immunohistochemistry. Our investigations provide e vidence that mRNA and protein expression of MMP-1, MMP-2, and TIMP-1 w ere significantly increased in lipodermatosclerosis, whereas the total amount of MMP-9 and TIMP-2 mRNA and protein was not altered. Western blot of liposclerotic lesions revealed an inactive proMMP-1-TIMP-1 com plex, whereas MMP-2 was prominent as an active 66 kDa band. Increased proteolytic activity of MMP-2 could be proven in lesional in compariso n with healthy skin by zymography and [H-3]collagen degradation. Incre ased diffuse staining was found for MMP-1 in the epidermis and dermis in comparison with controls. In lipodermatosclerosis, MMP-2 was predom inantly localized in the basal and suprabasal layers of the epidermis, in perivascular regions, and in the reticular part of the dermis, Fur thermore, MMP-2 was imbalanced by locally reduced expression of TIMP-2 in the basement membrane zone of lesional skin. Our findings indicate lipodermatosclerosis to be characterized by elevated matrix turnover.