Dr. Milner and Mr. Patel contributed equally to this work.
Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis
Article first published online: 30 MAR 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 62, Issue 7, pages 1955–1966, July 2010
How to Cite
Milner, J. M., Patel, A., Davidson, R. K., Swingler, T. E., Desilets, A., Young, D. A., Kelso, E. B., Donell, S. T., Cawston, T. E., Clark, I. M., Ferrell, W. R., Plevin, R., Lockhart, J. C., Leduc, R. and Rowan, A. D. (2010), Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis & Rheumatism, 62: 1955–1966. doi: 10.1002/art.27476
- Issue published online: 29 JUN 2010
- Article first published online: 30 MAR 2010
- Manuscript Accepted: 19 MAR 2010
- Manuscript Received: 14 DEC 2009
- Arthritis Research UK. Grant Numbers: 17165, 17728, 16006
- Biotechnology and Biological Sciences Research Council
- Newcastle Biomedical Research Centre
- Carnegie Trust
- Medical Research Council
- JGWP Foundation
- Dunhill Medical Trust
- Canadian Institutes of Health Research
- Chercheur National of the Fonds de la Recherche en Santé du Québec
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).
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.
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.
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.