Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway

Wang Hui, Gary J. Litherland, Matthew Jefferson, Matt J. Barter, Martina S. Elias, Tim E. Cawston, Andrew D. Rowan, David A. Young

Research output: Contribution to journalArticle

Abstract

Methods. The release of collagen was assessed in bovine cartilage explant cultures, whereas collagenolytic activities (active and total) in conditioned culture supernatants were determined by bioassay. The expression and production of MMP from chondrocytes were analysed by real-time RT-PCR and ELISA. Signalling pathway analysis was performed using a phospho-antibody array and standard immunoblotting.

Results. LiCl, but not selective glycogen synthase kinase 3 (GSK-3) inhibitor compounds SB-415286 and TDZD-8, significantly decreased pro-inflammatory cytokine-induced collagen release from bovine cartilage via the down-regulation of collagenolytic activity. Furthermore, MMP-1 and MMP-13 expression was reduced in both bovine and human chondrocytes. Pathway analysis revealed that LiCl selectively inhibited activation of the p38 mitogen-activated protein kinase pathway; effects that were recapitulated by specific p38 pathway inhibition.

Conclusions. This study demonstrates for the first time that LiCl can protect against cartilage damage induced by pro-inflammatory cytokines, and indicates that LiCl-mediated cartilage protection is not via a GSK-3-dependent mechanism, but potentially via inhibition of the p38 pathway. These data indicate that lithium administration may represent a potential therapy for arthritis.
Original languageEnglish
Pages (from-to)2043-2053
JournalRheumatology
Volume49
Issue number11
DOIs
Publication statusPublished - Nov 2010
Externally publishedYes

Keywords

  • Osteoarthritis
  • Chondrocytes
  • Lithium
  • p38
  • Gene expression

Cite this

Hui, Wang ; Litherland, Gary J. ; Jefferson, Matthew ; Barter, Matt J. ; Elias, Martina S. ; Cawston, Tim E. ; Rowan, Andrew D. ; Young, David A. / Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway. In: Rheumatology. 2010 ; Vol. 49, No. 11. pp. 2043-2053.
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abstract = "Methods. The release of collagen was assessed in bovine cartilage explant cultures, whereas collagenolytic activities (active and total) in conditioned culture supernatants were determined by bioassay. The expression and production of MMP from chondrocytes were analysed by real-time RT-PCR and ELISA. Signalling pathway analysis was performed using a phospho-antibody array and standard immunoblotting. Results. LiCl, but not selective glycogen synthase kinase 3 (GSK-3) inhibitor compounds SB-415286 and TDZD-8, significantly decreased pro-inflammatory cytokine-induced collagen release from bovine cartilage via the down-regulation of collagenolytic activity. Furthermore, MMP-1 and MMP-13 expression was reduced in both bovine and human chondrocytes. Pathway analysis revealed that LiCl selectively inhibited activation of the p38 mitogen-activated protein kinase pathway; effects that were recapitulated by specific p38 pathway inhibition. Conclusions. This study demonstrates for the first time that LiCl can protect against cartilage damage induced by pro-inflammatory cytokines, and indicates that LiCl-mediated cartilage protection is not via a GSK-3-dependent mechanism, but potentially via inhibition of the p38 pathway. These data indicate that lithium administration may represent a potential therapy for arthritis.",
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author = "Wang Hui and Litherland, {Gary J.} and Matthew Jefferson and Barter, {Matt J.} and Elias, {Martina S.} and Cawston, {Tim E.} and Rowan, {Andrew D.} and Young, {David A.}",
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Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway. / Hui, Wang; Litherland, Gary J.; Jefferson, Matthew; Barter, Matt J.; Elias, Martina S.; Cawston, Tim E.; Rowan, Andrew D.; Young, David A.

In: Rheumatology, Vol. 49, No. 11, 11.2010, p. 2043-2053.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway

AU - Hui, Wang

AU - Litherland, Gary J.

AU - Jefferson, Matthew

AU - Barter, Matt J.

AU - Elias, Martina S.

AU - Cawston, Tim E.

AU - Rowan, Andrew D.

AU - Young, David A.

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N2 - Methods. The release of collagen was assessed in bovine cartilage explant cultures, whereas collagenolytic activities (active and total) in conditioned culture supernatants were determined by bioassay. The expression and production of MMP from chondrocytes were analysed by real-time RT-PCR and ELISA. Signalling pathway analysis was performed using a phospho-antibody array and standard immunoblotting. Results. LiCl, but not selective glycogen synthase kinase 3 (GSK-3) inhibitor compounds SB-415286 and TDZD-8, significantly decreased pro-inflammatory cytokine-induced collagen release from bovine cartilage via the down-regulation of collagenolytic activity. Furthermore, MMP-1 and MMP-13 expression was reduced in both bovine and human chondrocytes. Pathway analysis revealed that LiCl selectively inhibited activation of the p38 mitogen-activated protein kinase pathway; effects that were recapitulated by specific p38 pathway inhibition. Conclusions. This study demonstrates for the first time that LiCl can protect against cartilage damage induced by pro-inflammatory cytokines, and indicates that LiCl-mediated cartilage protection is not via a GSK-3-dependent mechanism, but potentially via inhibition of the p38 pathway. These data indicate that lithium administration may represent a potential therapy for arthritis.

AB - Methods. The release of collagen was assessed in bovine cartilage explant cultures, whereas collagenolytic activities (active and total) in conditioned culture supernatants were determined by bioassay. The expression and production of MMP from chondrocytes were analysed by real-time RT-PCR and ELISA. Signalling pathway analysis was performed using a phospho-antibody array and standard immunoblotting. Results. LiCl, but not selective glycogen synthase kinase 3 (GSK-3) inhibitor compounds SB-415286 and TDZD-8, significantly decreased pro-inflammatory cytokine-induced collagen release from bovine cartilage via the down-regulation of collagenolytic activity. Furthermore, MMP-1 and MMP-13 expression was reduced in both bovine and human chondrocytes. Pathway analysis revealed that LiCl selectively inhibited activation of the p38 mitogen-activated protein kinase pathway; effects that were recapitulated by specific p38 pathway inhibition. Conclusions. This study demonstrates for the first time that LiCl can protect against cartilage damage induced by pro-inflammatory cytokines, and indicates that LiCl-mediated cartilage protection is not via a GSK-3-dependent mechanism, but potentially via inhibition of the p38 pathway. These data indicate that lithium administration may represent a potential therapy for arthritis.

KW - Osteoarthritis

KW - Chondrocytes

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KW - Gene expression

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