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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 Activity¹

^a Departments of Obstetrics and Gynecology and Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160

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.

First decision: 5 February 2001.

¹ Supported by a grant award (HD37941) from the Office of Research on Women's Health in conjunction with the NICHD and core support from NICHD center grant HD33994.

² Correspondence: Warren B. Nothnick, University of Kansas Medical Center, Department of Obstetrics and Gynecology, 3901 Rainbow Blvd., Kansas City, KS 66160. FAX: 913 588 6271; wnothnic{at}kumc.edu

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