The Metalloproteases Meprin α and β: Pathophysiological Roles in Inflammation, Cardiovascular Disease, Cancer, and Fibrosis

The metalloproteases meprin α and β exhibit unique functions in health and disease. Belonging to the metzincin superfamily, the meprins are two out of seven astacin zinc-endopeptidases in humans, representing the largest secreted protease known (oligomerized meprin α) and the only membrane-bound family member (meprin β). Meprins activate or release growth factors (e.g. IL-1β, IL-18, TGFα, and VEGF-A) and other biologically active peptides, and are involved in inflammatory diseases, such as Crohn's disease or ulcerative colitis. In vitro, both proteases exhibit gelatinolytic activity, revealing a possible link to tumor progression and metastasis. This is supported by cellular evidence from meprin β knockout mice, in which macrophage migration through the extracellular matrix was diminished. However, in fibrotic skin it has been demonstrated that meprin α and β enhance matrix assembly, by cleaving off the propeptides of fibrillar collagen. Hence, fundamental knowledge of their biological activity is necessary to assess meprin metalloproteases as therapeutic targets. For example, the meprin inhibitor actinonin, a naturally occurring hydroxamate derivate, has been shown to be protective against acute renal failure, a pathology strongly related to meprin activity.