Matrix metalloproteinases belong to a family of structurally related enzymes that plays important role in tissue morphogenesis, differentiation, and wound healing. Their expression is negatively regulated by several members of the steroid hormone receptor family. This is thought to occur through interaction of the steroid receptors with the transcription factor AP-1 that is otherwise required for positive regulation. Here, we demonstrate that AP-1 is not always a target for downregulation of expression of matrix metalloproteinases by steroid receptors. Androgen receptor negatively regulates matrix metalloproteinase-1 expression not through AP-1 but through a family of Ets-related transcription factors that are also required for positive regulation. This negative regulation is specific for the androgen receptor. It does not require the DNA binding activity but needs amino-terminal sequences of the receptor. These results identify a novel regulatory pathway for negative regulation utilized by a member of the steroid hormone receptor family for down-regulating the expression of matrix metalloproteinases.Matrix metalloproteinases (MMPs) 1 are composed of a family of metal-ion requiring enzymes that degrades components of the extracellular matrix. They can be subdivided into several classes on the basis of their substrate specificity. These classes include the interstitial collagenases, which degrade type I, II, and III collagens, the type IV collagenases, which degrade basement membrane collagens type IV and V, the stromelysins, which degrade proteoglycans, fibronectin, and laminin, and matrilysin, which has a wide range of substrates including proteoglycans, fibronectin, gelatin, and elastin (for reviews see Refs. 1 and 2).Regulated expression of MMPs accompanies changes in tissue organization in normal growth processes and pathological conditions. These are most evident in organogenesis, neovascularization, tissue repair, inflammation, arthritis, tumor invasion, and metastasis (1). In these processes, positive and negative regulation of expression of MMP genes by a variety of growth factors, cytokines, oncogenes, tumor promoters, and steroid hormones are required (2, 3). The steroid hormones in particular, negatively regulate the expression of the MMPs through the action of their corresponding receptors (4, 5).Glucocorticoid receptor (GR) exerts its negative regulation by interacting with the transcription factor AP-1, an important regulator of expression of several MMP genes (4 -8). Progesterone acting through its receptor in stromal cells of the endometrium down-regulates the levels of MMP mRNAs of the stromelysin family through a mechanism that is not yet known (9, 10). In the epithelial cells of the endometrium, progesterone down-regulates the expression of matrilysin through the release of transforming growth factor 1 from the stromal cells (10). Although androgen receptor (AR) represses the expression of several genes (11-17), it is not clear how this is effected nor is it clear whether MMPs belong to the...