Metalloproteinases mediate extracellular matrix degradation by cells from mouse blastocyst outgrowths.
The maintenance and developmental remodeling of extracellular matrix is crucial to such processes as uterine implantation and the cell migratory events of morphogenesis. When mouse blastocysts are placed in culture they adhere to extracellular matrix, and trophoblast giant cells migrate out onto the matrix and degrade it. The secretion of functional proteinases by developing mouse embryos increases dramatically at the time of implantation. By zymography we identified the major secreted gelatin-degrading proteinase, also known as type IV collagenase, as one migrating at 92 x 10(3) Mr. Several casein-degrading proteinases were also secreted. The tissue inhibitor of metalloproteinases (TIMP) inhibited all of the embryo-derived proteinases detected by gelatin gel zymography, indicating that they are metalloproteinases, whereas TIMP did not inhibit all of the caseinases. Urokinase was also secreted. Addition of TIMP at 5-500 nM effectively inhibited the degradation of matrix by the trophoblast outgrowths. Blocking antibodies directed against 92 x 10(3) Mr gelatinase abolished matrix degradation by the trophoblast cells. These observations suggest that several metalloproteinases are regulated in early development and that 92 x 10(3) Mr gelatinase, in particular, has a rate-limiting function in degradation of the maternal extracellular matrix by trophoblast cells.
Behrendtsen
O
O
Department of Anatomy, University of California, San Francisco 94143-0750.
Alexander
C M
CM
Werb
Z
Z
D000818:Animals; D001755:Blastocyst / Q000201:enzymology / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D010064:Embryo Implantation / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005341:Fibrinolysin / Q000494:pharmacology; D018093:Gelatinases; D006023:Glycoproteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D010434:Pepsin A / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases
D006023:Glycoproteins; D019714:Tissue Inhibitor of Metalloproteinases; D005341:Fibrinolysin; D010434:Pepsin A; D018093:Gelatinases; D008666:Metalloendopeptidases