Abstract
In inflamed joints, enhanced hyaluronic acid (HA) degradation is closely related to the pathogenesis of rheumatoid arthritis (RA). KIAA1199 has been identified as a hyaladherin that mediates the intracellular degradation of HA, but its extracellular function remains unclear. In this study, we found that the serum and synovial levels of secreted KIAA1199 (sKIAA1199) and low-molecular-weight HA (LMW-HA, MW < 100 kDa) in RA patients were significantly increased, and the positive correlation between them was shown for the first time. Of note, treatment with anti-KIAA1199 mAb effectively alleviated the severity of arthritis and reduced serum LMW-HA levels and cytokine secretion in collagen-induced arthritis (CIA) mice. In vitro, sKIAA1199 was shown to mediate exogenous HA degradation by attaching to the cell membrane of RA fibroblast-like synoviosytes (RA FLS). Furthermore, the HA-degrading activity of sKIAA1199 depended largely on its adhesion to the membrane, which was achieved by its G8 domain binding to ANXA1. In vivo, kiaa1199-KO mice exhibited greater resistance to collagen-induced arthritis. Interestingly, this resistance could be partially reversed by intra-articular injection of vectors encoding full-length KIAA1199 instead of G8-deleted KIAA119 mutant, which further confirmed the indispensable role of G8 domain in KIAA1199 involvement in RA pathological processes. Mechanically, the activation of NF-κB by interleukin-6 (IL-6) through PI3K/Akt signaling is suggested to be the main pathway to induce KIAA1199 expression in RA FLS. In conclusion, our study supported the contribution of sKIAA1199 to RA pathogenesis, providing a new therapeutic target for RA by blocking sKIAA1199-mediated HA degradation.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by pain, swelling, bone and cartilage destruction, and leading to joint disability[1]
In inflamed joints, hyaluronic acid (HA) metabolic disorder is suggested to be related to the pathogenesis of RA, the mechanism is not fully understood
We demonstrated for the first time that KIAA1199 and LMW-HA levels were positively correlated in clinical serum and synovial fluids
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by pain, swelling, bone and cartilage destruction, and leading to joint disability[1]. Native HA (n-HA) with high molecular weight (HMW, MW > 1000 kDa) in synovial fluid normally functions as a lubricant and a barrier to cytokines. Excessive low-molecular-weight HA (LMW-HA, MW < 100 kD) produced by intensified n-HA degradation exerts pro-inflammatory and pro-angiogenic effects[4,5]. HA size is thought to be largely determined by its catabolism[6], the exact mechanism of HA degradation in inflamed joints is still not fully understood. Hyaluronidases (HYALs) and oxygen-derived free radicals were generally accepted as two main causes of LMW-HA accumulation in synovial fluid of RA patients[2]
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