MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS AT THE OVINE TROPHOBLAST UTERINE INTERFACE

Trophoblast invasiveness in ruminants is limited to fusion of migratin g binucleate o cells with uterine epithelium, but considerable tissue remodelling and angiogenesis occurs within the endometrium at implanta tion. 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 stroma l, but not epithelial, cells and expression of proMMP-1 and proMMP-3 i s inhibited by interferon tau, the dominant preimplantation trophoblas t product, independently of its effects on prostaglandin production. M essenger RNA for TIMP-1 and TIMP-2 is expressed in endometrium through out the oestrous cycle and early pregnancy. Both TIMP-1 mRNA (0.9 kb t ranscript) and TIMP-2, mRNA (1.0kb 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 fr om day 16 and is undetectable on day 20. Uterine flushings from both n onpregnant and pregnant ewes on day 16 after oestrus contain proMMP-2, possibly transudated from plasma, and proMMP-9, but concentrations ar e higher in pregnancy. These enzymes are also detected in conditioned medium following culture of trophoblasts at days 16-20. Whether the tr ophoblast MMPs have a role in implantation in sheep remains to be esta blished. The production of MMPs and TIMPs in the endometrium and the c hanges associated with implantation events suggest that they contribut e to the marked endometrial remodelling associated with early placenta tion.