Misato Hashizume and Masahiko Mihara
Background: Blockade of inflammatory cytokines such as IL-1β, IL-6, and TNF-α inhibits the progression of joint damage in hands and feet in Rheumatoid Arthritis (RA). However, it has been recently reported that TNF inhibitors have little effect on the large weight-bearing joints once joint destruction has started. On the other hand, intraarticular injection of high-molecular-weight sodium Hyaluronate (HA) prevents cartilage degeneration in the large weight-bearing joints in osteoarthritis.
Objectives: We examined the effects of combinations of cytokine inhibitor and HA on the expression of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), MMPs (matrix metalloproteinases), and RANKL (receptor activator of nuclear factor κB ligand), which all play important roles in joint damage, in human RA fibroblastlike synoviocytes (RA-FLS) and chondrocytes.
Methods: RA-FLS and chondrocytes were cultured for 24 h in the presence of synovial fluid from active RA patients (CRP>12 mg/dL, n=5) with or without HA, IL-1 receptor antagonist, soluble TNF receptor-Fc (etanercept), and anti-IL-6 receptor antibody (tocilizumab). After culture, the levels of ADAMTS-4, MMP-3, and RANKL mRNA were measured by real-time PCR.
Results: RA synovial fluids induced ADAMTS-4,MMP-3, and RANKL mRNA expressions in RA-FLS and chondrocytes. Cytokine inhibitors partially inhibited ADAMTS-4,MMP-3, and RANKL mRNA expressions, showing that several cytokines are involved in the expression of joint destruction factors. The RA synovial fluids contained IL-1β, IL-6, soluble IL-6 receptor, and TNF-α. HA also partially inhibited ADAMTS-4,MMP-3, and RANKL mRNA expressions. Use of each cytokine inhibitor in combination with HA inhibited the production of these factors further than monotherapy with either.
Conclusions: Our results indicate that HA may be useful in preventing joint damage in large weight-bearing joints in RA patients. Furthermore, the concomitant use of cytokine inhibitors and HA might be of greater benefit for preserving cartilage function in RA patients.