Overexpression of the Matrix Metalloproteinase Matrilysin Results in Premature Mammary Gland Differentiation and Male Infertility

Abstract

To examine the role of matrilysin (MAT), an epithelial cell-specific matrix metalloproteinase, in the normal development and function of reproductive tissues, we generated transgenic animals that overexpress MAT 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, active, and inactive forms of the human MAT protein could be produced in an in vitro culture system, mutations of the MAT cDNA significantly decreased the efficiency with which the MAT protein was produced in vivo. Therefore, animals carrying the wild-type MAT transgene that expressed high levels of human MAT in vivo were further examined. Mammary glands from female transgenic animals were morphologically normal throughout mammary development, but displayed an increased ability to produce ␤-casein protein in virgin animals. In addition, beginning at approximately 8 mo of age, the testes of male transgenic animals became disorganized with apparent disintegration of interstitial tissue that normally surrounds the seminiferous tubules. The disruption of testis morphology was concurrent with the onset of infertility. These results suggest that overexpression of the matrix-degrading enzyme MAT alters the integrity of the extracellular matrix and thereby induces cellular differentiation and cellular destruction in a tissue-specific manner. INTRODUCTIONThe matrix metalloproteinases (MMPs) 1 are a family of extracellular proteases thought to be responsible for normal matrix remodeling and pathological tissue destruction by virtue of their ability to catabolize extracellular matrix components (Birkedael-Hansen et al., 1993; Hulboy et al., 1997 for review). The expression pattern of MMPs in normal tissues suggests that they are particularly involved in the remodeling associated with reproductive processes, including menstruation, trophoblast invasion, mammary gland morphogenesis, and involution of the uterus, mammary gland, and prostate . Studies with natural and synthetic inhibitors of MMPs (Brannstrom et al., 1988;Butler et al., 1991;Talhouk et al., 1992;Marbaix et al., 1996) and recent experiments that utilized genetically altered mice that express altered MMP substrates (Liu et al., 1995) or lack specific MMP family members (Rudolph-Owen et al., 1997) have confirmed the importance of MMPs in reproductive processes in several systems.Sixteen MMP family members have been described (reviewed in Hulboy et al., 1997; see also Cossins et al., 1996;Puente et al., 1996). All MMPs described have three essential domains: a signal sequence or predomain to direct secretion from the cell, a pro sequence to maintain latency, and a catalytic domain containing the critical zinc-binding site. Matrilysin (MAT, uterine (Birkedael-Hansen et al., 1993 for review). This and other domains found in specific MMP family members generate diversity by modifying properties such as substrate specificity, interaction with endogenous inh...

Locally produced relaxin may affect testis and vas deferens function in rats

“…MMP7 presents a broad spectrum of actions (reviewed in Ii et al (2006)), including a role in apoptosis, cell proliferation, and release of growth factors. In the male reproductive tract, it has been demonstrated that MMP7 is important for testicular integrity and fertility (Rudolph-Owen et al 1998), and it is present in human semen (Riccioli et al 2005). Our immunohistochemical studies show that MMP7 expression is expressed only in epithelial cells of the vas deferens.…”

Why are epididymal tumours so rare?

“…130 This unusual presence in epithelial cells suggests that the protein is involved in tissue development rather than tumourigenesis; 131 indeed, transgenic mice overexpressing MMP7 in the epididymis exhibit the protein in a structurally normal organ. 132 Erythropoietin promotes tumour growth Figure 3 Representative factors found in the epididymis that are involved in pro-cancer and tumour suppression mechanisms in cancer-prone tissues. Tumours follow transformation of a susceptible cell type to a potentially cancerous form (via proliferation) that can either be suppressed (immune suppression) or remain dormant until conditions allow progression into malignant tissues (by immune escape).…”

“…154 The pro-angiogenic erythropoietin is, however, upregulated by acute hypoxia in the mouse epididymis. 132 Constitutively-expressed HIF protein in the epididymis should enhance glycolysis under normal situations, rather than in hypoxia as occurs in other tissues. The epididymis does glycolyse aerobically and the rate does not increase under anaerobic conditions-it secretes lactate under both conditions.…”

Matrilysin (Matrix Metalloproteinase-7) Mediates E-Cadherin Ectodomain Shedding in Injured Lung Epithelium

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