| Matrix metalloproteinase enzymes (MMPs) play a role in many normal biological and pathogenic processes by degrading and remodeling the extracellular matrix. In reproductive tissues, MMPs are involved in ovarian function and endometrial remodeling during embryo implantation and menstruation. Other laboratories found endometrial MMP-3 expression to be down-regulated by progesterone (Schatz et al., 1994b). This was in sharp contrast to our observations showing that an in vivo progesterone dominated environment up-regulated MMP-3 production in subsequent tissue explant cultures. Therefore, we designed studies to determine the nature of these contradictory observations. We discovered that explant culture of the uterine endometrial tissue resulted in up-regulation of MMP-3 mRNA and protein in a steroid independent manner. Interestingly, explant culture did not alter MMP-3 mRNA or protein expression by endometriotic lesion explants.; We used an established rat endometriosis model to study MMP-3 mRNA levels in uterine and endometriotic lesions. Tissues were evaluated as they were recovered from the body (in vivo expression), after tissue explant culture (in vitro expression), and also by isolated uterine and endometriotic cell culture. Our experiments demonstrated that MMP-3 mRNA regulation depended on both tissue type and culture.; Increased MMP-3 mRNA expression was associated with an increase in interleukin-1α (IL-1α) expression by uterine tissue in explant culture. Little or no IL-1α mRNA was found in the in vivo samples, correlating with the absence or low levels of MMP-3 mRNA. Interestingly, levels of IL-1α were elevated in both in vivo and in vitro endometriotic lesion samples and might account for the persistent MMP-3 expression observed in these lesions.; We have found that IL-1α appears to regulate MMP-3 through several transcription factor binding sites on the MMP-3 promoter. These sites include AP-1, Ets and TGF-β. IL-1α also seems to interact with progesterone to modify the MMP-3 promoter binding of the transcription factor complexes. This suggests that MMP regulation might be occurring through changes in the amount of transcription factor binding. |
