Effect of matrix metalloproteinase inhibitors on rat embryo development in vitro

Matrix metalloproteinases appear to play a role in cell migration and tissue remodeling and are postulated to be important in the development of embryos. We hypothesized that inhibition of these proteinases with the synthetic inhibitor batimastat or with endogenous tissue inhibitor of metalloproteinases (TIMP) would alter in vitro development of day 9 rat embryos. Batimastat had a dose-related effect on embryo growth and viability following 48 h in culture, with significant inhibition at 1.0 microM concentration. Dying cells were observed in many organs of living embryos. TIMP-2 at 3.0 microg/ml had a similar effect on embryo growth. TIMP-1 alone or used in combination with TIMP-2 had no obvious effect. No focal malformations were observed. The effective concentrations are comparable to those which inhibit enzyme activity in cell culture. We conclude that matrix metalloproteinases are probably important in mammalian embryo development.