Differential Toll-like receptor-dependent collagenase expression in chondrocytes

Q. Zhang, W. Hui, G. J. Litherland, M. J. Barter, R. Davidson, C. Darrah, S. T. Donell, I. M. Clark, T. E. Cawston, J. H. Robinson, A. D. Rowan, D. A. Young

Research output: Contribution to journalArticle

Abstract

Objectives: To characterise the catabolic response of osteoarthritic chondrocytes to Toll-like receptor (TLR) ligands.

Methods: Induction of the collagenases, matrix metalloproteinase (MMP)1 and MMP13, by TLR ligands was assessed in chondrocytes by real-time reverse transcriptase (RT)-PCR. TLR signalling pathway activation and their involvement in collagenase induction were confirmed by immunoblotting and use of pathway inhibitors and siRNA. TLR expression was compared in the femoral head cartilage of normal controls and patients with osteoarthritis (OA) by real-time RT-PCR.

Results: Ligands for TLR6/2 and TLR3 showed the greatest upregulation of MMP1 and MMP13 respectively, although all TLR ligands upregulated these MMPs. MMP1 and MMP13 induction by TLR3 and TLR1/2 or TLR6/2 ligands were dependent on Trif and MyD88, respectively. These inductions were dependent upon the nuclear factor (NF)κB pathway, but were differentially inhibited by various mitogen-activated protein kinase inhibitors, with MMP13 induction most reliant on the extracellular signal-regulated kinase pathway. In addition, ligands for TLR1/2 and TLR6/2, but not TLR3, induced significant collagenolysis in a cartilage resorption assay. Finally, TLR2 was significantly downregulated and TLR3 upregulated in OA, compared to normal, cartilage.

Conclusions: Activation of chondrocyte TLRs leads to differential collagenase gene activation. Treatment of chondrocytes with TLR1/2 or TLR6/2 ligands resulted in collagen resorption. The modulated expression of chondrocyte TLR2 and TLR3 in OA cartilage, compared to normal, may reflect a response to repair cartilage or prevent further extracellular matrix destruction. These data suggest modulation of TLR-mediated signalling as a potential therapeutic strategy for the treatment of OA.
Original languageEnglish
Pages (from-to)1633-1641
JournalAnnals of the Rheumatic Diseases
Volume67
Issue number11
DOIs
Publication statusPublished - Nov 2008
Externally publishedYes

Cite this

Zhang, Q. ; Hui, W. ; Litherland, G. J. ; Barter, M. J. ; Davidson, R. ; Darrah, C. ; Donell, S. T. ; Clark, I. M. ; Cawston, T. E. ; Robinson, J. H. ; Rowan, A. D. ; Young, D. A. / Differential Toll-like receptor-dependent collagenase expression in chondrocytes. In: Annals of the Rheumatic Diseases. 2008 ; Vol. 67, No. 11. pp. 1633-1641.
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title = "Differential Toll-like receptor-dependent collagenase expression in chondrocytes",
abstract = "Objectives: To characterise the catabolic response of osteoarthritic chondrocytes to Toll-like receptor (TLR) ligands.Methods: Induction of the collagenases, matrix metalloproteinase (MMP)1 and MMP13, by TLR ligands was assessed in chondrocytes by real-time reverse transcriptase (RT)-PCR. TLR signalling pathway activation and their involvement in collagenase induction were confirmed by immunoblotting and use of pathway inhibitors and siRNA. TLR expression was compared in the femoral head cartilage of normal controls and patients with osteoarthritis (OA) by real-time RT-PCR.Results: Ligands for TLR6/2 and TLR3 showed the greatest upregulation of MMP1 and MMP13 respectively, although all TLR ligands upregulated these MMPs. MMP1 and MMP13 induction by TLR3 and TLR1/2 or TLR6/2 ligands were dependent on Trif and MyD88, respectively. These inductions were dependent upon the nuclear factor (NF)κB pathway, but were differentially inhibited by various mitogen-activated protein kinase inhibitors, with MMP13 induction most reliant on the extracellular signal-regulated kinase pathway. In addition, ligands for TLR1/2 and TLR6/2, but not TLR3, induced significant collagenolysis in a cartilage resorption assay. Finally, TLR2 was significantly downregulated and TLR3 upregulated in OA, compared to normal, cartilage.Conclusions: Activation of chondrocyte TLRs leads to differential collagenase gene activation. Treatment of chondrocytes with TLR1/2 or TLR6/2 ligands resulted in collagen resorption. The modulated expression of chondrocyte TLR2 and TLR3 in OA cartilage, compared to normal, may reflect a response to repair cartilage or prevent further extracellular matrix destruction. These data suggest modulation of TLR-mediated signalling as a potential therapeutic strategy for the treatment of OA.",
author = "Q. Zhang and W. Hui and Litherland, {G. J.} and Barter, {M. J.} and R. Davidson and C. Darrah and Donell, {S. T.} and Clark, {I. M.} and Cawston, {T. E.} and Robinson, {J. H.} and Rowan, {A. D.} and Young, {D. A.}",
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doi = "10.1136/ard.2007.079574",
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Zhang, Q, Hui, W, Litherland, GJ, Barter, MJ, Davidson, R, Darrah, C, Donell, ST, Clark, IM, Cawston, TE, Robinson, JH, Rowan, AD & Young, DA 2008, 'Differential Toll-like receptor-dependent collagenase expression in chondrocytes' Annals of the Rheumatic Diseases, vol. 67, no. 11, pp. 1633-1641. https://doi.org/10.1136/ard.2007.079574

Differential Toll-like receptor-dependent collagenase expression in chondrocytes. / Zhang, Q.; Hui, W.; Litherland, G. J.; Barter, M. J.; Davidson, R.; Darrah, C.; Donell, S. T.; Clark, I. M.; Cawston, T. E.; Robinson, J. H.; Rowan, A. D.; Young, D. A.

In: Annals of the Rheumatic Diseases, Vol. 67, No. 11, 11.2008, p. 1633-1641.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential Toll-like receptor-dependent collagenase expression in chondrocytes

AU - Zhang, Q.

AU - Hui, W.

AU - Litherland, G. J.

AU - Barter, M. J.

AU - Davidson, R.

AU - Darrah, C.

AU - Donell, S. T.

AU - Clark, I. M.

AU - Cawston, T. E.

AU - Robinson, J. H.

AU - Rowan, A. D.

AU - Young, D. A.

PY - 2008/11

Y1 - 2008/11

N2 - Objectives: To characterise the catabolic response of osteoarthritic chondrocytes to Toll-like receptor (TLR) ligands.Methods: Induction of the collagenases, matrix metalloproteinase (MMP)1 and MMP13, by TLR ligands was assessed in chondrocytes by real-time reverse transcriptase (RT)-PCR. TLR signalling pathway activation and their involvement in collagenase induction were confirmed by immunoblotting and use of pathway inhibitors and siRNA. TLR expression was compared in the femoral head cartilage of normal controls and patients with osteoarthritis (OA) by real-time RT-PCR.Results: Ligands for TLR6/2 and TLR3 showed the greatest upregulation of MMP1 and MMP13 respectively, although all TLR ligands upregulated these MMPs. MMP1 and MMP13 induction by TLR3 and TLR1/2 or TLR6/2 ligands were dependent on Trif and MyD88, respectively. These inductions were dependent upon the nuclear factor (NF)κB pathway, but were differentially inhibited by various mitogen-activated protein kinase inhibitors, with MMP13 induction most reliant on the extracellular signal-regulated kinase pathway. In addition, ligands for TLR1/2 and TLR6/2, but not TLR3, induced significant collagenolysis in a cartilage resorption assay. Finally, TLR2 was significantly downregulated and TLR3 upregulated in OA, compared to normal, cartilage.Conclusions: Activation of chondrocyte TLRs leads to differential collagenase gene activation. Treatment of chondrocytes with TLR1/2 or TLR6/2 ligands resulted in collagen resorption. The modulated expression of chondrocyte TLR2 and TLR3 in OA cartilage, compared to normal, may reflect a response to repair cartilage or prevent further extracellular matrix destruction. These data suggest modulation of TLR-mediated signalling as a potential therapeutic strategy for the treatment of OA.

AB - Objectives: To characterise the catabolic response of osteoarthritic chondrocytes to Toll-like receptor (TLR) ligands.Methods: Induction of the collagenases, matrix metalloproteinase (MMP)1 and MMP13, by TLR ligands was assessed in chondrocytes by real-time reverse transcriptase (RT)-PCR. TLR signalling pathway activation and their involvement in collagenase induction were confirmed by immunoblotting and use of pathway inhibitors and siRNA. TLR expression was compared in the femoral head cartilage of normal controls and patients with osteoarthritis (OA) by real-time RT-PCR.Results: Ligands for TLR6/2 and TLR3 showed the greatest upregulation of MMP1 and MMP13 respectively, although all TLR ligands upregulated these MMPs. MMP1 and MMP13 induction by TLR3 and TLR1/2 or TLR6/2 ligands were dependent on Trif and MyD88, respectively. These inductions were dependent upon the nuclear factor (NF)κB pathway, but were differentially inhibited by various mitogen-activated protein kinase inhibitors, with MMP13 induction most reliant on the extracellular signal-regulated kinase pathway. In addition, ligands for TLR1/2 and TLR6/2, but not TLR3, induced significant collagenolysis in a cartilage resorption assay. Finally, TLR2 was significantly downregulated and TLR3 upregulated in OA, compared to normal, cartilage.Conclusions: Activation of chondrocyte TLRs leads to differential collagenase gene activation. Treatment of chondrocytes with TLR1/2 or TLR6/2 ligands resulted in collagen resorption. The modulated expression of chondrocyte TLR2 and TLR3 in OA cartilage, compared to normal, may reflect a response to repair cartilage or prevent further extracellular matrix destruction. These data suggest modulation of TLR-mediated signalling as a potential therapeutic strategy for the treatment of OA.

U2 - 10.1136/ard.2007.079574

DO - 10.1136/ard.2007.079574

M3 - Article

VL - 67

SP - 1633

EP - 1641

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 11

ER -