title: Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis.
abstract: OBJECTIVE
  Increasing evidence implicates serine proteinases in pathologic tissue turnover. The aim of this study was to assess the role of the transmembrane serine proteinase matriptase in cartilage destruction in osteoarthritis (OA).
  
  
  METHODS
  Serine proteinase gene expression in femoral head cartilage obtained from either patients with hip OA or patients with fracture to the neck of the femur (NOF) was assessed using a low-density array. The effect of matriptase on collagen breakdown was determined in cartilage degradation models, while the effect on matrix metalloproteinase (MMP) expression was analyzed by real-time polymerase chain reaction. ProMMP processing was determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis/N-terminal sequencing, while its ability to activate proteinase-activated receptor 2 (PAR-2) was determined using a synovial perfusion assay in mice.
  
  
  RESULTS
  Matriptase gene expression was significantly elevated in OA cartilage compared with NOF cartilage, and matriptase was immunolocalized to OA chondrocytes. We showed that matriptase activated proMMP-1 and processed proMMP-3 to its fully active form. Exogenous matriptase significantly enhanced cytokine-stimulated cartilage collagenolysis, while matriptase alone caused significant collagenolysis from OA cartilage, which was metalloproteinase-dependent. Matriptase also induced MMP-1, MMP-3, and MMP-13 gene expression. Synovial perfusion data confirmed that matriptase activates PAR-2, and we demonstrated that matriptase-dependent enhancement of collagenolysis from OA cartilage is blocked by PAR-2 inhibition.
  
  
  CONCLUSIONS
  Elevated matriptase expression in OA and the ability of matriptase to activate selective proMMPs as well as induce collagenase expression make this serine proteinase a key initiator and inducer of cartilage destruction in OA. We propose that the indirect effects of matriptase are mediated by PAR-2, and a more detailed understanding of these mechanisms may highlight important new therapeutic targets for OA treatment.
authors.affiliation: Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Milner
authors.forename: Amit
authors.initials: A
authors.lastname: Patel
authors.forename: Rose K
authors.initials: RK
authors.lastname: Davidson
authors.forename: Tracey E
authors.initials: TE
authors.lastname: Swingler
authors.forename: Antoine
authors.initials: A
authors.lastname: Desilets
authors.forename: David A
authors.initials: DA
authors.lastname: Young
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Kelso
authors.forename: Simon T
authors.initials: ST
authors.lastname: Donell
authors.forename: Tim E
authors.initials: TE
authors.lastname: Cawston
authors.forename: Ian M
authors.initials: IM
authors.lastname: Clark
authors.forename: William R
authors.initials: WR
authors.lastname: Ferrell
authors.forename: Robin
authors.initials: R
authors.lastname: Plevin
authors.forename: John C
authors.initials: JC
authors.lastname: Lockhart
authors.forename: Richard
authors.initials: R
authors.lastname: Leduc
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rowan
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology*; D002417:Cattle; D019902:Chondrocytes / Q000201:enzymology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005265:Femoral Neck Fractures / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015207:Osteoarthritis, Hip / Q000201:enzymology*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D053491:Proteinase Inhibitory Proteins, Secretory; D044464:Receptor, PAR-2; C109149:SPINT1 protein, human; D012697:Serine Endopeptidases; C485595:matriptase; D020782:Matrix Metalloproteinases