TISSUE INHIBITOR OF METALLOPROTEINASES (TIMP)-1, (TIMP)-2 AND (TIMP)-3 IN HUMAN ENDOMETRIUM DURING THE MENSTRUAL-CYCLE

The extensive remodelling of the human endometrium throughout the mens trual cycle is accompanied by changes in production of matrix metallop roteinases, the activity of which can be inhibited by specific tissue inhibitors or by tissue inhibitors of metalloproteinases (TIMP)s with a 1:1 stoichiometry. This study immunolocalized TIMP-1, TIMP-2 and TIM P-3 in dated normal human endometrium across the menstrual cycle and e xamined cultured endometrial cells for their production. All three TIM Ps were present in the major cellular compartments, luminal epithelium , glands, stroma, endothelial cells and vascular smooth muscle cells w ith the most intense immunoreactivity in the luminal epithelium. TIMP- 1 and -3 were Tower in the mid-to-late proliferative phase with a nadi r of TIMP-3 particularly in the late proliferative phase. Decidualized stromal cells stained strongly positive for TIMP-1, -2 and -3. Cells of haematopoietic origin never stained. Monensin treatment of tissue r esulted in accumulation of TIMPs in all cellular compartments but part icularly of TIMP-1 in epithelium. Cultured endometrial stromal cells r eleased more TIMP-1 than TIMP-2 or TIMP-3 into culture medium and all were increased following decidualization in vitro. Epithelial cells in culture produced less TIMPs than stromal cells, and only a few epithe lial cells in each culture were immunopositive for TIMP-1. The ubiquit ous distribution of TlMPs implicates them in maintenance of endometria l integrity, with changes in the matrix metalloproteinases without con comitant changes in TIMPs determining endometrial matrix degradation.