Missing the target: matrix metalloproteinase antitargets in inflammation and cancer

Abstract

Matrix metalloproteinases (MMPs) are reputed to cause the inflammatory tissue destruction characterizing chronic inflammatory diseases and to degrade basement membrane collagen, thereby facilitating cancer cell metastasis. However, following the disappointing MMP drug cancer trials, recent studies using mouse models of disease coupled with high-throughput methods for substrate discovery have revealed surprising and unexpected new biological roles of MMPs in inflammatory diseases and cancer in vivo. Thus, MMPs modify signaling pathways and regulate the activity of whole families of cytokines of the immune response by precise proteolytic processing. By cleaving and inactivating cytokine-binding proteins and protease inhibitors, cytokine activities are unmasked and activities of diverse proteases are increased in an interconnected protease web. With new substrates come new roles, and 10 of 24 murine MMPs have antitumorigenic and anti-inflammatory roles making them drug antitargets; that is, their beneficial actions should not be inhibited. Here, we examine whether the discovery that MMPs are drug antitargets for one disease might pave the way for their use for other indications or whether this is a serious threat to the development of MMP inhibitors.