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Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory synovitis that leads to the destruction of bone and cartilage. The receptor for advanced glycation end products (RAGE) is a multiligand membrane-bound receptor for high-mobility group box-1 (HMGB1) associated with development of RA by inducing production of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6. We developed a bone-targeting therapeutic agent by tagging acidic oligopeptide to a nonmembrane-bound form of RAGE (endogenous secretory RAGE [esRAGE]) functioning as a decoy receptor. We assessed its tissue distribution and therapeutic effectiveness in a murine model of collagen-induced arthritis (CIA). Acidic oligopeptide-tagged esRAGE (D6-esRAGE) was localized to mineralized region in bone, resulting in the prolonged retention of more than 1 wk. Weekly administration of D6-esRAGE with a dose of 1 mg/kg to RA model mice significantly ameliorated inflammatory arthritis, synovial hyperplasia, cartilage destruction and bone destruction, while untagged esRAGE showed little effectiveness. Moreover, D6-esRAGE reduced plasma levels of proinflammatory cytokines including TNF-α, IL-1 and IL-6, while esRAGE reduced the levels of IL-1 and IL-6 to a lesser extent, suggesting that production of IL-1 and IL-6 reduced along the blockade of HMGB1 receptor downstream signals by D6-esRAGE could be attributed to remission of CIA. These findings indicate that D6-esRAGE enhances drug delivery to bone, leading to rescue of clinical and pathological lesions in murine CIA.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory synovitis dominated by the presence of macrophages, lymphocytes and synovial fibroblasts, leading to the destruction of bone and cartilage [1]
Untagged endogenous secretory RAGE (esRAGE) was endogenously truncated at the C-terminus, which is involved in membrane penetration, and was secreted into the culture medium when stably expressed in CHOK1 cells
The acidic oligopeptide–tagged esRAGEs (D6-esRAGE, D10-esRAGE and D14-esRAGE), in which a stretch of acidic oligopeptide was introduced at C-terminus of esRAGE, were secreted into the culture medium as well
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory synovitis dominated by the presence of macrophages, lymphocytes and synovial fibroblasts, leading to the destruction of bone and cartilage [1]. The introduction of novel biologics has revolutionized RA treatment. Their success has underlined the key roles of proinflammatory cytokines in the pathogenesis of inflammatory arthritis, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1 and IL-6 [2,3,4]. This approach enhances the specificity in their effects but diminishes adverse events. Some patients did not respond to even such advanced biologic agents. Because the pathogenesis of RA is caused by multiple complex factors involving a wide range of molecules, the factors other than TNF-α, IL-1 and IL-6 participate in the proinflammatory cytokine cascade
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