Inactivating mutation of the mouse tissue inhibitor of metalloproteinases-2(Timp-2) gene alters proMMP-2 activation

To understand the biologic function of TIMP-2, a member of the tissue inhib itors of metalloproteinases family, an inactivating mutation was introduced in the mouse Timp-2 gene by homologous recombination, Outbred homozygous m utants developed and procreated indistinguishably from wild type littermate s, suggesting that fertility, development, and growth are not critically de pendent on TIMP-2, Lack of functional TIMP-2, however, dramatically altered the activation of proMMP-2 both in vivo and in vitro. Fully functional TIM P-2 is essential for efficient activation of proMMP-2 in vivo, No evidence of successful functional compensation was observed. The results illustrate the duality of TIMP-2 function, i.e. at low concentrations, TIMP-2 exerts a "catalytic" or enhancing effect on cell-mediated proMMP-2 activation, wher eas at higher concentrations, TIMP-2 inhibits the activation and/or activit y of MMP-2.