Effect of Matrix Metalloproteinase Inhibitors on Rat Embryo Development in vitro

Abstract

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 μM concentration. Dying cells were observed in many organs of living embryos. TIMP-2 at 3.0 μg/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.

Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats

“…Determining the gene and protein expression patterns of MMPs targeted by prinomastat at different stages of embryonic development would provide greater insight into the specific MMPs responsible for the fetal abnormalities observed. Batimastat, a broad MMP inhibitor, has also been shown to perturb embryo growth and viability when exposed to rat embryo cultures (Del Bigio and Seyoum, 1999). The correlation among the in vitro and in vivo studies present herein and by others (Del Bigio and Seyoum, 1999) further supports that the aberrations on embryogenesis and fetal development are a direct result of MMPs inhibition in the embryo and not due to maternal toxicities.…”

“…Batimastat, a broad MMP inhibitor, has also been shown to perturb embryo growth and viability when exposed to rat embryo cultures (Del Bigio and Seyoum, 1999). The correlation among the in vitro and in vivo studies present herein and by others (Del Bigio and Seyoum, 1999) further supports that the aberrations on embryogenesis and fetal development are a direct result of MMPs inhibition in the embryo and not due to maternal toxicities. The expression of MMP throughout embryogenesis and fetal development and the subsequent perturbations produced on these systems by inhibiting MMP activity are consistent with our findings.…”

Role of hypoxia‐induced fibronectin‐integrin β1 expression in embryonic stem cell proliferation and migration: Involvement of PI3K/Akt and FAK

“…Consistent with our observations, it has recently been reported that inhibition of MMP‐2 or ‐9 significantly suppresses migration of human cancer cells and human cervical cancer cells (Chen et al, 2010; Maity et al, 2010). The participation of MMPs in the proliferation of ESCs could provide the basis to understand the mechanisms of early embryonic development and suggests that therapies based on MMP inhibition could be applied to embryo dysfunction (Del Bigio and Seyoum, 1999). In addition, the inhibition of IN β1 activity using IN β1 antibody blocked the hypoxia‐induced increase in cell‐cycle regulatory proteins (CDK 2/4 and cyclin D1/E) and DNA synthesis.…”