Degradation of the collagenous extracellular matrix by metalloproteases (MMPs) plays an important role in the pathogenesis of osteoarthritis (OA). Recently, it was suggested that endothelin 1 (ET-1), a potent vasoconstrictor, may be involved in MMP regulation. This study investigated the role of ET-1 in OA cartilage degradation.
We explored ET-1 expression and synthesis in normal and OA cartilage and synovial membrane by reverse transcription-polymerase chain reaction and immunohistochemistry. MMP-1 and MMP-13 gene expression and protein synthesis were investigated using Northern blotting and enzyme-linked immunosorbent assays. Additionally, ET-1-induced collagenase activity, type II collagen metabolites, and tissue inhibitor of metalloproteases 1 (TIMP-1) protein were evaluated.
We found expression and synthesis of ET-1, in situ, in both normal and OA cartilage and synovial membrane. We demonstrated that ET-1 induced gene expression and protein synthesis of both MMP-1 and MMP-13. These enzymes were produced in OA chondrocyte cultures, and the production increased in a dose-dependent manner in the presence of ET-1. In OA cartilage, ET-1 also induced type II collagen-derived neoepitopes concomitantly with an increase in collagenase activity and a decrease in TIMP-1 protein.
Our results provide strong evidence of the catabolic role of ET-1 in OA cartilage via MMP-1 and MMP-13 up-regulation. As well, ET-1 increased the net MMP/TIMP balance and secondarily increased collagen degradation. Hence, ET-1 becomes an attractive factor to target in the conception of new therapeutic approaches for OA and other diseases in which MMP-13 and MMP-1 actions are crucial in tissue alteration.