Membrane-type matrix metalloproteinase 1 regulates trophoblast functions and is reduced in fetal growth restriction

Fetal growth restriction (FGR) results from placental insufficiency to adequately supply the fetus. This insufficiency involves impaired cytotrophoblast functions, including reduced migration and invasion, proliferation, and syncytium formation. Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a key enzyme in these cellular processes. MT1-MMP exists in various forms: a 63-kDa proenzyme is synthesized as primary translation product, which is cleaved into a 57-kDa membrane-anchored active form. We hypothesized that reduced placental MT1-MMP in FGR impairs trophoblast functions. MT1-MMP mRNA and active enzyme was quantified in placentas from FGR and age-matched control pregnancies. MT1-MMP protein was localized in first-trimester and term placentas. Putative MT1-MMP functions in trophoblasts were determined using two blocking antibodies for measuring migration and proliferation, as well as fusion of primary trophoblasts and trophoblast-derived cells. MT1-MMP was expressed predominantly in the syncytiotrophoblast and the villous and extravillous cytotrophoblasts. In FGR placentas, levels of MT1-MMP mRNA and of active MT1-MMP protein were reduced (-34.2%, P < 0.05, and -21.5%, P < 0.01, respectively), compared with age-matched controls. MT1-MMP-blocking antibodies diminished migration, proliferation, and trophoblast fusion. We conclude that reduced placental MT1-MMP in FGR may contribute to the impaired trophoblast functions associated with this pathology.