Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation.
Gelatinase B, a matrix metalloproteinase (MMP) of high specific activity, is highly expressed and activated by mouse blastocysts in culture, and inhibition of this enzyme activity inhibits lysis of extracellular matrix (Behrendtsen, O., Alexander, C. M. and Werb, Z. (1992) Development 114, 447-456). Because gelatinase B expression is linked to invasive potential, we studied the expression of gelatinase B mRNA and protein in vivo, in implanting trophoblast giant cells, and found that it was expressed and activated during colonization of the maternal decidua. mRNAs for several other MMPs (stromelysin-1, stromelysin-3 and gelatinase A) and MMP inhibitors (TIMP-1 and TIMP-2) were expressed in the undifferentiated stroma toward the outside of the decidua, and TIMP-3 mRNA was expressed in primary and some mature decidual cells during their differentiation. Both mRNA and TIMP-3 protein were present at high concentrations transiently, and declined from 6.5 days post coitum onward, as the cells underwent apoptosis during the main period of gelatinase B expression and ectoplacental growth and expansion. To assess the function of MMPs during implantation and decidual development, we either injected a peptide hydroxamate MMP inhibitor into normal mice or studied transgenic mice overexpressing TIMP-1. In both cases, decidual length and overall size were reduced, and the embryo was displaced mesometrially. Embryo orientation was less strictly regulated in inhibitor-treated deciduae than in control deciduae. Morphogenesis and development of oil-induced deciduomas were also slowed in the presence of the inhibitor. We conclude that administration of MMP inhibitors retards decidual remodeling and growth, and we suggest that the MMPs expressed in precursor stromal cells promote their differentiation and expansion.
Alexander
C M
CM
Laboratory of Radiobiology, Department of Biopharmaceutical Sciences, University of California, San Francisco, 94143, USA.
Hansell
E J
EJ
Behrendtsen
O
O
Flannery
M L
ML
Kishnani
N S
NS
Hawkes
S P
SP
Werb
Z
Z
D000818:Animals; D017209:Apoptosis; D001755:Blastocyst / Q000201:enzymology; D002454:Cell Differentiation; D017364:Collagenases / Q000235:genetics / Q000502:physiology; D003656:Decidua / Q000201:enzymology*; D004624:Embryo Transfer; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology*; D005109:Extracellular Matrix / Q000201:enzymology; D005260:Female; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D017154:Stromal Cells / Q000201:enzymology; D019716:Tissue Inhibitor of Metalloproteinase-2; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D014327:Trophoblasts / Q000201:enzymology
D006023:Glycoproteins; D061965:Matrix Metalloproteinase Inhibitors; D011506:Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9