Molecular Medicine

, Volume 19, Issue 1, pp 183–194 | Cite as

Bone-Targeting Endogenous Secretory Receptor for Advanced Glycation End Products Rescues Rheumatoid Arthritis

  • Tatsuo Takahashi
  • Sayaka Katsuta
  • Yusuke Tamura
  • Nozomi Nagase
  • Keita Suzuki
  • Masaaki Nomura
  • Shunji Tomatsu
  • Ken-ichi Miyamoto
  • Shinjiro Kobayashi
Research Article


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 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 (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.



This work was supported by a grant-in-aid (type B) for young scientists, number 20790150, from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Editorial assistance was provided by Michelle Stofa at the Nemours/Alfred I. duPont Hospital for Children.


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Authors and Affiliations

  • Tatsuo Takahashi
    • 1
  • Sayaka Katsuta
    • 1
  • Yusuke Tamura
    • 1
  • Nozomi Nagase
    • 1
  • Keita Suzuki
    • 1
  • Masaaki Nomura
    • 2
  • Shunji Tomatsu
    • 3
    • 4
  • Ken-ichi Miyamoto
    • 5
  • Shinjiro Kobayashi
    • 1
  1. 1.Department of Clinical Pharmacy, Faculty of Pharmaceutical SciencesHokuriku UniversityKanazawaJapan
  2. 2.Educational Center of Clinical Pharmacy, Faculty of Pharmaceutical SciencesHokuriku UniversityKanazawaJapan
  3. 3.Department of Biomedical ResearchNemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  4. 4.Department of Pediatric Orthopedic SurgeryNemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  5. 5.Department of Medicinal Informatics, Graduate School of Medical SciencesKanazawa UniversityKanazawaJapan

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