title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Osteoarthritis Research Unit, Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Roy-Beaudry
authors.forename: Johanne
authors.initials: J
authors.lastname: Martel-Pelletier
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pelletier
authors.forename: Khatija Nait
authors.initials: KN
authors.lastname: M'Barek
authors.forename: Stephan
authors.initials: S
authors.lastname: Christgau
authors.forename: Fazool
authors.initials: F
authors.lastname: Shipkolye
authors.forename: Florina
authors.initials: F
authors.lastname: Moldovan
mesh_terms: D000328:Adult; D002356:Cartilage / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D024043:Collagen Type II / Q000378:metabolism; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics* / Q000494:pharmacology; D000939:Epitopes; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology
chemical_list: D024043:Collagen Type II; D019332:Endothelin-1; D000939:Epitopes; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1