Matrix metalloproteinases and their tissue inhibitors at the ovine trophoblast-uterine interface

Trophoblast invasiveness in ruminants is limited to fusion of migrating binucleate cells with uterine epithelium, but considerable tissue remodelling and angiogenesis occurs within the endometrium at implantation. Such processes are elsewhere associated with an altered balance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). ProMMPs-1, -2, -3 are secreted by cultured ovine endometrial stromal, but not epithelial, cells and expression of proMMP-1 and proMMP-3 is inhibited by interferon tau, the dominant preimplantation trophoblast product, independently of its effects on prostaglandin production. Messenger RNA for TIMP-1 and TIMP-2 is expressed in endometrium throughout the oestrous cycle and early pregnancy. Both TIMP-1 mRNA (0.9 kb transcript) and TIMP-2 mRNA (1.0 kb transcript) expression increase at day 12 through to day 20, suggesting a role in preventing trophoblast invasion. Expression of the 3.5 kb transcript for TIMP-2 decreases from day 16 and is undetectable on day 20. Uterine flushings from both nonpregnant and pregnant ewes on day 16 after oestrus contain proMMP-2, possibly transudated from plasma, and proMMP-9, but concentrations are higher in pregnancy. These enzymes are also detected in conditioned medium following culture of trophoblasts at days 16-20. Whether the trophoblast MMPs have a role in implantation in sheep remains to be established. The production of MMPs and TIMPs in the endometrium and the changes associated with implantation events suggest that they contribute to the marked edometrial remodelling associated with early placentation.