TNFα cleavage beyond TACE/ADAM17: matrix metalloproteinase 13 is a potential therapeutic target in sepsis and colitis

» ...pro-inflammatory activity of MMP13 not by ‘simply’ degrading extracellular matrix but through the release of biologically active soluble TNFa from its membrane bound precursor form. « For decades, matrix metalloproteinases (MMPs) have been described as rather unspecific matrix‐ and collagen‐degrading enzymes. Accordingly, this group of proteases was mainly associated with tissue remodeling and pathologic conditions such as tumour development and metastasis. However, broad spectrum MMP inhibitors completely failed in cancer therapy. Recent studies with gene deficient mice revealed more specific functions of MMPs, e.g. the cleavage of chemokines, thereby stimulating inflammatory responses (Dufour & Overall, 2013). Additionally, mass spectrometry‐based proteomic techniques allowed for the identification of hundreds of new substrates of MMPs, giving rise to unexpected biological activity of these proteases in health and disease. MMP13 is known to be one of few collagenases capable of cleaving rigid collagen fibrils. This ability is based on a complex unfolding mechanism of the triple‐helical collagen structure. Therefore, MMP13 biology is well studied in