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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/R1630    most recent 00380.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Harslund, J. Articles by Offenberg, H. Search for Related Content PubMed PubMed Citation Articles by Harslund, J. Articles by Offenberg, H.

DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Gender-dependent physiological implications of combined PAI-1 and TIMP-1 gene deficiency characterized in a mouse model

¹Section of Biomedicine and ²Section of Pathology, Department of Veterinary Pathobiology, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark

Submitted 31 May 2007 ; accepted in final form 19 July 2007

The endogenous proteinase inhibitors plasminogen activator inhibitor type 1 (PAI-1) and tissue inhibitor of metalloproteinase type 1 (TIMP-1) are two distinct proteins with separate molecular pathways. However, a close relationship between PAI-1 and TIMP-1 has been proposed indicating some degree of functional overlap due to their involvement in ECM turnover, tissue remodeling, and cellular migration and signaling. To study the housekeeping physiological implications of PAI-1 and TIMP-1, we generated a combined PAI-1 and TIMP-1 gene-deficient mouse model. We present the results on generating this specific mouse model with particular emphasis on phenotypical characteristics, blood leukocyte counts, histology, and gene expression studies of PAI-1 and TIMP-1 in various organs. We observed a significant deviation in segregation of offspring only in male mice (P < 0.01) predominantly caused by PAI-1 deficiency. In addition, the body weight in 3- and 20-wk-old male and 20-wk-old female mice was significantly different between genotypes (P 0.0008). Furthermore, blood leukocyte counts were significantly different between genotypes in 20-wk-old male mice (P 0.0002), whereas no significant differences were observed between genotypes in 20-wk-old female mice (P 0.13). Quantifying the relative expression of PAI-1 and TIMP-1 revealed upregulation of PAI-1 (P < 0.001) in male mice only. Our data highlight the complex roles of PAI-1 and TIMP-1 on physiological parameters such as segregation of offspring (embryonic development and survival), body weight (metabolism), blood leukocyte counts (immunity), and gene expression (regulatory redundancy). We conclude that PAI-1 and TIMP-1 seem to possess gender-dependent regulatory properties on various housekeeping physiological parameters and stress the potential implications in pathological conditions.

body weight; blood leukocyte count; gene expression; plasminogen activator inhibitor type 1; tissue inhibitor of metalloproteinase type 1