Submitted on May 31, 2007
Accepted on July 19, 2007
Gender-dependent physiological implications of combined PAI-1 and TIMP-1 gene deficiency characterized in a mouse model
Jakob Harslund1*, Ole Lerberg Nielsen2, Nils Brunner3, and Hanne Offenberg3
1 Biomedicin, Inst. of Veterinary Pathobiolgy, Frederiksberg C, Denmark
2 Pathology, Inst. of Veterinary Pathobiology, Frederiksberg C, Denmark
3 Frederiksberg C, Denmark; Biomedicin, Inst. of Veterinary Pathobiolgy, Frederiksberg C, Denmark
* To whom correspondence should be addressed. E-mail: jhar{at}life.ku.dk.
The endogenous proteinase inhibitors PAI-1 and 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 remodelling and cellular migration and signalling. To study the house-keeping physiological implications of PAI-1 and TIMP-1 we have 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 (p0.0002), while 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 house-keeping physiological parameters and stress the potential implications in pathological conditions.
