Evaluation of intracellular signal molecules that regulate TLR4-stimulated inflammatory mediator expression in cultured rat chondrocytes

Osteoarthritis (OA) is characterized by inflammation of joints and degradation of articular cartilage matrix. As involvement of damage-associated molecular patterns (DAMPs) in the pathogenesis of OA has been reported, the present study comprehensively investigated the regulation of inflammatory mediator expression in chondrocytes mediated by Toll-like receptor 4 (TLR4), a receptor for DAMPs. Treatment of cultured rat chondrocytes with lipopolysaccharide (LPS) induced the mRNA expression of proinflammatory cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]), matrix degradation enzymes (metalloproteinase [MMP] 3, MMP13), and inducible nitric oxide synthase (iNOS) through TLR4. Transforming growth factor β-activated kinase-1 (TAK1) and nuclear factor-κB (NF-κB) were crucial for the upregulated expression of these inflammatory mediators. The induction of IL-1β and TNF was regulated by extracellular signal-regulated kinase (ERK), while the induction of IL-6 was mediated by Tank-binding kinase 1 (TBK1) and c-Jun N-terminal kinase (JNK). The induction of MMP3 and MMP13 was regulated by TBK1, ERK, and JNK, while the induction of iNOS was mediated by ERK and JNK. In summary, some of the regulatory mechanisms underlying the expression of key inflammatory mediators for OA pathogenesis have been demonstrated. Further clarification may allow these signaling molecules to become new therapeutic targets for OA treatment strategies.