Endothelin 1 promotes osteoarthritic cartilage degradation via matrix metalloprotease 1 and matrix metalloprotease 13 induction

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Abstract
Objective 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. Methods 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. Results 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. Conclusion 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.
Funding Information
  • Canadian Institutes of Health Research (DSH-44200, MOP-57760)