The serine proteinase hepsin is an activator of pro-matrix metalloproteinases: molecular mechanisms and implications for extracellular matrix turnover

Increasing evidence implicates serine proteinases in the proteolytic cascades leading to the pathological destruction of extracellular matrices such as cartilage in osteoarthritis (OA). We have previously demonstrated that the type II transmembrane serine proteinase (TTSP) matriptaseacts as a novel initiator of cartilage destruction via the induction and activation of matrix metalloproteinases (MMPs). Hepsinis another TTSP expressed in OA cartilage such that we hypothesized this proteinase may also contribute to matrix turnover. Herein, we demonstrate that addition of hepsinto OA cartilage in explant cultureinduced significant collagen and aggrecanrelease and activated proMMP-1 and proMMP-3. Furthermore, hepsindirectly cleaved the aggrecancore protein at a novel cleavage site within the interglobular domain. Hepsinexpression correlated with synovitisas well as tumour necrosis factor α expression, and was induced in cartilage by a pro-inflammatory stimulus. However, a major difference compared to matriptasewas that hepsindemonstrated markedly reduced capacity to activate proteinase-activated receptor-2. Overall, our data suggest that hepsin, like matriptase, induces potent destruction of the extracellular matrix whilst displaying distinct efficiencies for the cleavage of specific substrates.