Reduction in reproductive lifespan of tissue inhibitor of metalloproteinase 1 (TIMP-1)-deficient female mice

Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a multifunctional protein expressed in the ovary and uterus of females of several species including mice, rats and humans. Mice deficient in TIMP-1 protein display altered reproductive parameters, which include reduced serum progesterone concentrations and abnormal uterine morphology. As these abnormalities could lead to altered reproductive performance, the objective of this study was to examine whether TIMP-1 deficiency is associated with a reduction in the reproductive lifespan of female mice in which the TIMP-1 gene is disrupted. Wild-type (n = 50) and TIMP-1 null mice (n = 90) were mated with males of proven fertility from the same genotype for 12 months during which the number of litters delivered and the number of pups per litter were determined. Significantly fewer TIMP-1 null females achieved pregnancy (47 of 90 or 52%) compared with the wild-type mice (39 of 50 or 78%; P < 0.05). TIMP-1-deficient female mice that achieved and maintained pregnancy had significantly fewer litters during the 12 months (2.9 +/- 0.8 versus 3.5 +/- 0.8; P < 0.01) and significantly fewer pups per litter (5.7 +/- 1.3 versus 4.7 +/- 1.1; P < 0.05) than did wild-type mice. Females of both genotypes produced two consecutive litters, after which significantly fewer TIMP-1 null mice became pregnant. Mating of females with males of proven fertility from the other genotype confirmed that these abnormalities were not due to the inability of TIMP-1 null males to produce offspring. These data indicate that the absence of TIMP-1 is associated with a reduction in the reproductive lifespan of female mice, which may be manifested at the ovary, uterus or both organs.