OVEREXPRESSION OF THE MATRIX METALLOPROTEINASE MATRILYSIN RESULTS IN PREMATURE MAMMARY-GLAND DIFFERENTIATION AND MALE-INFERTILITY

.To examine the role of matrilysin (MAT), an epithelial cell-specific matrix metalloproteinase, in the normal development and function of re productive tissues, we generated transgenic animals that overexpress M AT in several reproductive organs. Three distinct forms of human MAT ( wild-type, active, and inactive) were placed under the control of the murine mammary tumor virus promoter/enhancer. Although wild-type, acti ve, and inactive forms of the human MAT protein could be produced in a n in vitro culture system, mutations of the MAT cDNA significantly dec reased the efficiency with which the MAT protein was produced in vivo. Therefore, animals carrying the wild-type MAT transgene that expresse d high levels of human MAT in vivo were further examined. Mammary glan ds from female transgenic animals were morphologically normal througho ut mammary development, but displayed an increased ability to produce p-casein protein in virgin animals. In addition, beginning at approxim ately 8 mo of age, the testes of male transgenic animals became disorg anized with apparent disintegration of interstitial tissue that normal ly surrounds the seminiferous tubules. The disruption of testis morpho logy was concurrent with the onset of infertility. These results sugge st that overexpression of the matrix-degrading enzyme MAT alters the i ntegrity of the extracellular matrix and thereby induces cellular diff erentiation and cellular destruction in a tissue-specific manner.