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

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.

• Authors: Marjolaine Roy-Beaudry, Johanne Martel-Pelletier, Jean-Pierre Pelletier, Khatija Nait M'Barek, Stephan Christgau, Fazool Shipkolye, Florina Moldovan
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 48 Issue 10 Pg. 2855-64 (Oct 2003) ISSN: 0004-3591 [Print] United States
• PMID: 14558091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type II
• Endothelin-1
• Epitopes
• Collagenases
• MMP13 protein, human
• Matrix Metalloproteinase 13
• Matrix Metalloproteinase 1

Topics

• Adult
• Cartilage (enzymology, pathology, physiopathology)
• Collagen Type II (metabolism)
• Collagenases (genetics, metabolism)
• Endothelin-1 (genetics, pharmacology)
• Epitopes
• Gene Expression Regulation, Enzymologic (drug effects, physiology)
• Humans
• Matrix Metalloproteinase 1 (genetics, metabolism)
• Matrix Metalloproteinase 13
• Middle Aged
• Osteoarthritis (metabolism, pathology, physiopathology)
• Synovial Membrane (enzymology, pathology, physiopathology)