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

Abstract

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. 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. 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. 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.