Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis

Jennifer M. Milner, Amit Patel, Rose K. Davidson, Tracey E. Swingler, Antoine Desilets, David A. Young, Elizabeth B. Kelso, Simon T. Donell, Tim E. Cawston, Ian M. Clark, William R. Ferrell, Robin Plevin, John C. Lockhart, Richard Leduc, Andrew D. Rowan

Research output: Contribution to journalArticle

54 Citations (Scopus)

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.

Conclusion. 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.
Original languageEnglish
Pages (from-to)1955-1966
JournalArthritis and Rheumatism
Volume62
Issue number7
DOIs
Publication statusPublished - Jul 2010

Keywords

  • osteoarthritis
  • matriptase

Cite this

Milner, J. M., Patel, A., Davidson, R. K., Swingler, T. E., Desilets, A., Young, D. A., ... Rowan, A. D. (2010). Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis. Arthritis and Rheumatism, 62(7), 1955-1966. https://doi.org/10.1002/art.27476
Milner, Jennifer M. ; Patel, Amit ; Davidson, Rose K. ; Swingler, Tracey E. ; Desilets, Antoine ; Young, David A. ; Kelso, Elizabeth B. ; Donell, Simon T. ; Cawston, Tim E. ; Clark, Ian M. ; Ferrell, William R. ; Plevin, Robin ; Lockhart, John C. ; Leduc, Richard ; Rowan, Andrew D. / Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis. In: Arthritis and Rheumatism. 2010 ; Vol. 62, No. 7. pp. 1955-1966.
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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.Conclusion. 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.",
keywords = "osteoarthritis, matriptase",
author = "Milner, {Jennifer M.} and Amit Patel and Davidson, {Rose K.} and Swingler, {Tracey E.} and Antoine Desilets and Young, {David A.} and Kelso, {Elizabeth B.} and Donell, {Simon T.} and Cawston, {Tim E.} and Clark, {Ian M.} and Ferrell, {William R.} and Robin Plevin and Lockhart, {John C.} and Richard Leduc and Rowan, {Andrew D.}",
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Milner, JM, Patel, A, Davidson, RK, Swingler, TE, Desilets, A, Young, DA, Kelso, EB, Donell, ST, Cawston, TE, Clark, IM, Ferrell, WR, Plevin, R, Lockhart, JC, Leduc, R & Rowan, AD 2010, 'Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis', Arthritis and Rheumatism, vol. 62, no. 7, pp. 1955-1966. https://doi.org/10.1002/art.27476

Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis. / Milner, Jennifer M.; Patel, Amit; Davidson, Rose K.; Swingler, Tracey E.; Desilets, Antoine; Young, David A.; Kelso, Elizabeth B.; Donell, Simon T.; Cawston, Tim E.; Clark, Ian M.; Ferrell, William R. ; Plevin, Robin; Lockhart, John C.; Leduc, Richard; Rowan, Andrew D.

In: Arthritis and Rheumatism, Vol. 62, No. 7, 07.2010, p. 1955-1966.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis

AU - Milner, Jennifer M.

AU - Patel, Amit

AU - Davidson, Rose K.

AU - Swingler, Tracey E.

AU - Desilets, Antoine

AU - Young, David A.

AU - Kelso, Elizabeth B.

AU - Donell, Simon T.

AU - Cawston, Tim E.

AU - Clark, Ian M.

AU - Ferrell, William R.

AU - Plevin, Robin

AU - Lockhart, John C.

AU - Leduc, Richard

AU - Rowan, Andrew D.

PY - 2010/7

Y1 - 2010/7

N2 - 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.Conclusion. 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.

AB - 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.Conclusion. 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.

KW - osteoarthritis

KW - matriptase

U2 - 10.1002/art.27476

DO - 10.1002/art.27476

M3 - Article

VL - 62

SP - 1955

EP - 1966

JO - Arthritis and Rheumatism

JF - Arthritis and Rheumatism

SN - 0004-3591

IS - 7

ER -

Milner JM, Patel A, Davidson RK, Swingler TE, Desilets A, Young DA et al. Matriptase Is a Novel Initiator of Cartilage Matrix Degradation in Osteoarthritis. Arthritis and Rheumatism. 2010 Jul;62(7):1955-1966. https://doi.org/10.1002/art.27476