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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

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 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.

Notes

Acknowledgments

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.

References

  1. 1.
    Firestein GS. (2003) Evolving concepts of rheumatoid arthritis. Nature. 423:356–61.CrossRefGoogle Scholar
  2. 2.
    Choy EH, Panayi GS. (2001) Cytokine pathways and joint inflammation in rheumatoid arthritis. N. Engl. J. Med. 344:907–16.CrossRefPubMedGoogle Scholar
  3. 3.
    Feldmann M. (2002) Development of anti-TNF therapy for rheumatoid arthritis. Nat. Rev. Immunol. 2:364–71.CrossRefPubMedGoogle Scholar
  4. 4.
    Maini RN. (2010) Anti-TNF therapy from the bench to the clinic: a paradigm of translational research. Clin. Med. 10:161–2.CrossRefGoogle Scholar
  5. 5.
    Moreland LW, et al. (1999) Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann. Intern. Med. 130:478–86.CrossRefPubMedGoogle Scholar
  6. 6.
    Cohen S, et al. (2002) Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46:614–24.CrossRefPubMedGoogle Scholar
  7. 7.
    Maini RN, et al.; CHARISMA Study Group. (2006) Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum. 54:2817–29.CrossRefPubMedGoogle Scholar
  8. 8.
    Kokkola R, et al. (2002) High mobility group box chromosomal protein 1: a novel proinflammatory mediator in synovitis. Arthritis Rheum. 46:2598–603.CrossRefPubMedGoogle Scholar
  9. 9.
    Taniguchi N, et al. (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 48:971–81.CrossRefPubMedGoogle Scholar
  10. 10.
    Huttunen HJ, Fages C, Kuja-Panula J, Ridley AJ, Rauvala H. (2002) Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res. 62:4805–11.Google Scholar
  11. 11.
    van Beijnum JR, Buurman WA, Griffioen AW. (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis. 11:91–9.CrossRefGoogle Scholar
  12. 12.
    Huang JS, et al. (2001) Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J. Cell. Biochem. 81:102–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Zhou Z, et al. (2008) HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J. Bone Miner. Res. 23:1084–96.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Guo HF, et al. (2011) High mobility group box 1 induces synoviocyte proliferation in rheumatoid arthritis by activating the signal transducer and activator transcription signal pathway. Clin. Exp. Med. 11:65–74.CrossRefPubMedGoogle Scholar
  15. 15.
    Neeper M, et al. (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J. Biol. Chem. 267:14998–5004.PubMedGoogle Scholar
  16. 16.
    Hofmann MA, et al. (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 97:889–901.CrossRefGoogle Scholar
  17. 17.
    Huttunen HJ, Fages C, Rauvala H. (1999) Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J. Biol. Chem. 274:19919–24.CrossRefPubMedGoogle Scholar
  18. 18.
    Malherbe P, et al. (1999) cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein. Brain Res. Mol. Brain Res. 71:159–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Park IH, et al. (2004) Expression of a novel secreted splice variant of the receptor for advanced glycation end products (RAGE) in human brain astrocytes and peripheral blood mononuclear cells. Mol. Immunol. 40:1203–11.CrossRefPubMedGoogle Scholar
  20. 20.
    Yonekura H, et al. (2003) Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem. J. 370:1097–109.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Yonekura H, Yamamoto Y, Sakurai S, Watanabe T, Yamamoto H. (2005) Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury. J. Pharmacol. Sci. 97:305–11.CrossRefPubMedGoogle Scholar
  22. 22.
    Kasugai S, Fujisawa R, Waki Y, Miyamoto K, Ohya K. (2000) Selective drug delivery system to bone: small peptide (Asp)6 conjugation. J. Bone Miner. Res. 15:936–43.CrossRefPubMedGoogle Scholar
  23. 23.
    Yokogawa K, et al. (2001) Selective delivery of estradiol to bone by aspartic acid oligopeptide and its effects on ovariectomized mice. Endocrinology. 142:1228–33.CrossRefPubMedGoogle Scholar
  24. 24.
    Takahashi T, et al. (2008) Bone-targeting of quinolones conjugated with an acidic oligopeptide. Pharm. Res. 25:2881–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Oldberg A, Franzén A, Heinegård D. (1986) Cloning and sequence analysis of rat bone sialoprotein (osteopontin) cDNA reveals an Arg-Gly-Asp cell-binding sequence. Proc. Natl. Acad. Sci. U. S. A. 83:8819–23.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Butler WT. (1989) The nature and significance of osteopontin. Connect Tissue Res. 23:123–36.CrossRefPubMedGoogle Scholar
  27. 27.
    Nishioka T, et al. (2006) Enhancement of drug delivery to bone: characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide. Mol. Genet. Metab. 88:244–55.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Millán JL, et al. (2008) Enzyme replacement therapy for murine hypophosphatasia. J. Bone Miner. Res. 23:777–87.CrossRefPubMedGoogle Scholar
  29. 29.
    Montaño AM, et al. (2008) Acidic amino acid tag enhances response to enzyme replacement in mucopolysaccharidosis type VII mice. Mol. Genet. Metab. 94:178–89.CrossRefPubMedGoogle Scholar
  30. 30.
    Tomatsu S, et al. (2010) Enhancement of drug delivery: enzyme-replacement therapy for murine Morquio A syndrome. Mol. Ther. 18:1094–102.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Whyte MP, et al. (2012) Enzyme-replacement therapy in life-threatening hypophosphatasia. N. Engl. J. Med. 366:904–13.CrossRefPubMedGoogle Scholar
  32. 32.
    Trentham DE, Townes AS, Kang AH. (1977) Autoimmunity to type II collagen an experimental model of arthritis. J. Exp. Med. 146:857–68.CrossRefGoogle Scholar
  33. 33.
    Courtenay JS, Dallman MJ, Dayan AD, Martin A, Mosedale B. (1980) Immunisation against heterologous type II collagen induces arthritis in mice. Nature. 283:666–8.CrossRefGoogle Scholar
  34. 34.
    Williams RO, Feldmann M, Maini RN. (1992) Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. U. S. A. 89:9784–8.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Neurath MF, et al. (1999) Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): a mechanism for methotrexatemediated immunosuppression. Clin. Exp. Immunol. 115:42–55.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hori O, et al. (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin: mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J. Biol. Chem. 270:25752–61.CrossRefPubMedGoogle Scholar
  37. 37.
    Park JS, et al. (2006) High mobility group box 1 protein interacts with multiple Toll-like receptors. Am. J. Physiol. Cell Physiol. 290:C917–24.CrossRefGoogle Scholar
  38. 38.
    Hofmann MA, et al. (2002) RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response. Genes Immun. 3:123–35.CrossRefPubMedGoogle Scholar
  39. 39.
    Foell D, et al. (2003) Expression of the pro-inflammatory protein S100A12 (EN-RAGE) in rheumatoid and psoriatic arthritis. Rheumatology (Oxford). 42:1383–9.CrossRefGoogle Scholar
  40. 40.
    Chen YS, Yan W, Geczy CL, Brown MA, Thomas R. (2009) Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis. Arthritis Res. Ther. 11:R39.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    van Lent PL, et al. (2008) Stimulation of chondrocyte-mediated cartilage destruction by S100A8 in experimental murine arthritis. Arthritis Rheum. 58:3776–87.CrossRefPubMedGoogle Scholar
  42. 42.
    Turovskaya O, et al. (2008) RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis. 29:2035–43.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Srikrishna G, et al. (2010) Carboxylated N-glycans on RAGE promote S100A12 binding and signaling. J. Cell. Biochem. 110:645–59.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Srikrishna G, et al. (2002) N-Glycans on the receptor for advanced glycation end products influence amphoterin binding and neurite outgrowth. J. Neurochem. 80:998–1008.CrossRefPubMedGoogle Scholar
  45. 45.
    Lipsky PE, et al. (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis: AntiTumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N. Engl. J. Med. 343:1594–602.CrossRefPubMedGoogle Scholar
  46. 46.
    Weinblatt ME, et al. (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48:35–45.CrossRefPubMedGoogle Scholar
  47. 47.
    Campbell IK, O’Donnell K, Lawlor KE, Wicks IP. (2001) Severe inflammatory arthritis and lymphadenopathy in the absence of TNF. J. Clin. Invest. 107:1519–27.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pullerits R, Jonsson IM, Kollias G, Tarkowski A. (2008) Induction of arthritis by high mobility group box chromosomal protein 1 is independent of tumour necrosis factor signalling. Arthritis Res. Ther. 10:R72.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Saijo S, Asano M, Horai R, Yamamoto H, Iwakura Y. (2002) Suppression of autoimmune arthritis in interleukin-1-deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells. Arthritis Rheum. 46:533–44.CrossRefPubMedGoogle Scholar
  50. 50.
    Alonzi T, et al. (1998) Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187:461–8.CrossRefPubMedPubMedCentralGoogle Scholar

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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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