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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)-\u03b1, interleukin (IL)-1 and IL-6. We developed a bone-targeting therapeutic agent by tagging acidic oligopeptide to a nonmem-brane-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 (D<jats:sub>6<\/jats:sub>-esRAGE) was localized to mineralized region in bone, resulting in the prolonged retention of more than 1 wk. Weekly administration of D<jats:sub>6<\/jats:sub>-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, D<jats:sub>6<\/jats:sub>-esRAGE reduced plasma levels of proinflammatory cytokines including TNF-\u03b1, 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 D<jats:sub>6<\/jats:sub>-esRAGE could be attributed to remission of CIA. These findings indicate that D<jats:sub>6<\/jats:sub>-esRAGE enhances drug delivery to bone, leading to rescue of clinical and pathological lesions in murine CIA.<\/jats:p>","DOI":"10.2119\/molmed.2012.00309","type":"journal-article","created":{"date-parts":[[2013,8,15]],"date-time":"2013-08-15T01:06:00Z","timestamp":1376528760000},"page":"183-194","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Bone-Targeting Endogenous Secretory Receptor for Advanced Glycation End Products Rescues Rheumatoid Arthritis"],"prefix":"10.1186","volume":"19","author":[{"given":"Tatsuo","family":"Takahashi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayaka","family":"Katsuta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Tamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nozomi","family":"Nagase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keita","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masaaki","family":"Nomura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunji","family":"Tomatsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-ichi","family":"Miyamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinjiro","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2013,6,27]]},"reference":[{"key":"1901183_CR1","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nature01661","volume":"423","author":"GS Firestein","year":"2003","unstructured":"Firestein GS. 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