Lithium protects cartilage from cytokine-mediated degradation by reducing collagen-degrading MMP production via inhibition of the P38 mitogen-activated protein kinase pathway.
OBJECTIVE
To determine the effects and mechanism of action of lithium chloride (LiCl) on cartilage destruction induced by the pro-inflammatory cytokines IL-1, IL-1 + oncostatin M and TNF-α.


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.
Hui
Wang
W
Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, The Medical School, Framlington Place, Newcastle-upon-Tyne, UK.
Litherland
Gary J
GJ
Jefferson
Matthew
M
Barter
Matt J
MJ
Elias
Martina S
MS
Cawston
Tim E
TE
Rowan
Andrew D
AD
Young
David A
DA
D000368:Aged; D000818:Animals; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018021:Lithium Chloride / Q000378:metabolism / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases; D018021:Lithium Chloride