Progesterone inhibits activation of latent matrix metalloproteinase (MMP)-2 by membrane-type 1 MMP: Enzymes coordinately expressed in human endometrium

Matrix metalloproteinases (MMP) have specific spatial and temporal expressi on patterns in human endometrium and are critical for menstruation. Express ion and activation mechanisms for proMMP-2 differ from of her MMPs; in many cells proMMP-2 is specifically activated by membrane-type (MT)-MMPs. We ex amined the expression and localization of proMMP-2, MT1-MMP, and MT2-MMP in human endometrium across the menstrual cycle; and we examined the expressi on of MT1-MMP and activation of proMMP-2 in cultured endometrial stromal ce lls and their regulation by progesterone. MMP-2 was immunolocalized in 25 o f 32 endometrial samples in all cellular compartments but with greatest int ensity in degrading menstrual tissue. MT1-MMP mRNA was present throughout t he cycle, and immunoreactive protein was detected in 24 of 32 samples, with the strongest staining in subsets of macrophages, Fleutrophils, and granul ar lymphocytes (but not mast cells or eosinophils) during the menstrual, mi d-proliferative and mid-secretory phases. Patchy epithelial staining and st aining of decidual cells, often periglandular in menstrual tissue, were als o seen. MT2-MMP was more widespread than MT1-MMP without apparent cyclical variation and with maximal intensity in glandular epithelium. Cultured endo metrial stromal cells released proMMP-2 and progesterone treatment signific antly reduced the percentage level of ifs active (62 kDa) form (22.5 +/- 1. 8% vs. 3.0 +/- 1.3%, without and with treatment, respectively, mean +/- SEM , P < 0.0001). This activation was blocked by a specific MMP inhibitor and restored following inhibitor removal. Progesterone also attenuated cell exp ression of MT1-MMP mRNA. We postulate that MT1-MMP activates proMMP-2 in en dometrium, this activity being increased at the end of the cycle when proge sterone levels fall, thus contributing to menstruation.