Disruption of the tissue inhibitor of metalloproteinase-1 gene in reproductive-age female mice is associated with estrous cycle stage-specific increases in stromelysin messenger RNA expression and activity.
Tissue inhibitors of metalloproteinases (TIMPs) are expressed in the uteri of virtually all species, yet the precise role of these factors in uterine physiology is uncertain. It has been previously demonstrated that disruption of the TIMP-1 gene product in vivo results in altered reproductive cycles and an aberrant uterine phenotype. Because this phenotype may be due to an elevation in uterine matrix metalloproteinase (MMP) activity, the purpose of the following experiments was to identify which uterine MMPs may have their expression altered in response to disruption of the TIMP-1 gene. Mature female TIMP-1 wild-type and null mice were killed during each stage of the estrous cycle, and uterine MMP activity and transcript expression were assessed. Disruption of the TIMP-1 gene product was associated with an increase in total uterine protease activity. Gel zymography further revealed that uterine stromelysin (stromelysin-1, -2, and -3) activity was significantly increased in the TIMP-1 null mice, whereas Northern blot analysis indicated that an up-regulation of stromelysin-1 and -3 mRNA expression may contribute to this increase in activity. It is concluded from this study that TIMP-1 plays a pivotal role in regulating uterine stromelysins both at the level of protease activity and the level of transcript expression.
Nothnick
W B
WB
Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. wnothnic@kumc.edu
D000818:Animals; D015152:Blotting, Northern; D010450:Endopeptidases / Q000378:metabolism; D030762:Estrous Cycle; D005260:Female; D005786:Gene Expression Regulation; D053506:Matrix Metalloproteinase 10; D053507:Matrix Metalloproteinase 11; D019278:Matrix Metalloproteinase 3 / Q000235:genetics* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D014599:Uterus / Q000201:enzymology
D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D010450:Endopeptidases; D053507:Matrix Metalloproteinase 11; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D053506:Matrix Metalloproteinase 10