Skip to main content

Advertisement

SpringerLink
Log in

The effects of the receptor for advanced glycation end products (RAGE) on bone metabolism under physiological and diabetic conditions

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

It has been reported that AGEs and the receptor for AGEs (RAGEs) have been linked to the pathogenesis of diabetic microangiopathy. However, the relationship between RAGE and alteration in bone metabolism is unclear. Therefore, in order to determine the role of RAGE in bone metabolism, we investigated the effects of RAGE deletion on bone metabolism under physiological and diabetic conditions using RAGE knockout mice (RAGE-KO). Eight-week-old male RAGE-KO and wild-type littermates (WT) were intraperitoneally injected with either streptozotocin or vehicle. Mice were classified into four groups: (1) nondiabetic WT; (2) nondiabetic RAGE-KO; (3) diabetic WT; and (4) diabetic RAGE-KO. After 12 weeks of streptozotocin or vehicle treatment, the physical properties of femora and the static and dynamic parameters of bone histomorphometry of tibiae were assessed. The deletion of RAGE affected neither body weights nor hemoglobin A1c levels. RAGE deletion resulted in increased bone mineral density due to decreased osteoclast function under physiological conditions that is no accumulation of AGEs. In contrast, lacking RAGE did not affect the alteration in bone metabolism under diabetic conditions, suggesting that AGEs–RAGE interaction may not be involved in the pathogenesis of diabetic osteopenia, although RAGE plays a crucial role in bone metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. M.E. Levin, V.C. Boisseau, L.V. Avioli, Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes. N. Engl. J. Med. 294(5), 241–245 (1976)

    Article  PubMed  CAS  Google Scholar 

  2. L. Forsén, H.E. Meyer, K. Midthjell, T.H. Edna, Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trøndelag Health Survey. Diabetologia 42(8), 920–925 (1999)

    Article  PubMed  Google Scholar 

  3. A.M. Herskind, K. Christensen, K. Nørgaard-Andersen, J.F. Andersen, Diabetes mellitus and healing of closed fractures. Diabete Metab 18(1), 63–64 (1992)

    PubMed  CAS  Google Scholar 

  4. Y. Hamada, S. Kitazawa, R. Kitazawa, H. Fujii, M. Kasuga, M. Fukagawa, Histomorphometric analysis of diabetic osteopenia in streptozotocin-induced diabetic mice: a possible role of oxidative stress. Bone 40(5), 1408–1414 (2007)

    Article  PubMed  CAS  Google Scholar 

  5. H. Fujii, Y. Hamada, M. Fukagawa, Bone formation in spontaneously diabetic Torii-newly established model of non-obese type 2 diabetes rats. Bone 42(2), 372–379 (2008)

    Article  PubMed  CAS  Google Scholar 

  6. Y. Hamada, H. Fujii, R. Kitazawa, J. Yodoi, S. Kitazawa, M. Fukagawa, Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic osteopenia: a novel role of oxidative stress and therapeutic implications. Bone 44(5), 936–941 (2009)

    Article  PubMed  CAS  Google Scholar 

  7. Y. Hamada, H. Fujii, M. Fukagawa, Role of oxidative stress in diabetic bone disorder. Bone 45(Suppl 1), S35–S38 (2009)

    Article  PubMed  CAS  Google Scholar 

  8. M. Brownlee, Biochemistry and molecular cell biology of diabetic complications. Nature 414(6865), 813–820 (2001)

    Article  PubMed  CAS  Google Scholar 

  9. T. Miyata, K. Notoya, K. Yoshida, K. Horie, K. Maeda, K. Kurokawa et al., Advanced glycation end products enhance osteoclast-induced bone resorption in cultured mouse unfractionated bone cells and in rats implanted subcutaneously with devitalized bone particles. J. Am. Soc. Nephrol. 8(2), 260–270 (1997)

    PubMed  CAS  Google Scholar 

  10. M. Alikhani, Z. Alikhani, C. Boyd, C.M. MacLellan, M. Raptis, R. Liu et al., Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone 40(2), 345–353 (2007)

    Article  PubMed  CAS  Google Scholar 

  11. G. Hein, R. Wiegand, G. Lehmann, G. Stein, S. Franke, Advanced glycation end-products pentosidine and N epsilon-carboxymethyllysine are elevated in serum of patients with osteoporosis. Rheumatology 42(10), 1242–1246 (2003)

    Article  PubMed  CAS  Google Scholar 

  12. M. Shiraki, T. Kuroda, S. Tanaka, M. Saito, M. Fukunaga, T. Nakamura, Nonenzymatic collagen cross-links induced by glycoxidation (pentosidine) predicts vertebral fractures. J. Bone Miner. Metab. 26(1), 93–100 (2008)

    Article  PubMed  CAS  Google Scholar 

  13. A.M. Schmidt, M. Vianna, M. Gerlach, J. Brett, J. Ryan, J. Kao et al., Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J. Biol. Chem. 267(21), 14987–14997 (1992)

    PubMed  CAS  Google Scholar 

  14. M. Neeper, A.M. Schmidt, J. Brett, S.D. Yan, F. Wang, Y.C. Pan et al., Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J. Biol. Chem. 267(21), 14998–15004 (1992)

    PubMed  CAS  Google Scholar 

  15. J. Brett, A.M. Schmidt, S.D. Yan, Y.S. Zou, E. Weidman, D. Pinsky et al., Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am. J. Pathol. 143(6), 1699–1712 (1993)

    PubMed  CAS  Google Scholar 

  16. A.M. Schmidt, S.D. Yan, D.M. Stern, The dark side of glucose. Nat. Med. 1(10), 1002–1004 (1995)

    Article  PubMed  CAS  Google Scholar 

  17. W.F. Owen Jr., F.F. Hou, R.O. Stuart, J. Kay, J. Boyce, G.M. Chertow et al., β2-Microglobulin modified with advanced glycation end products modulates collagen synthesis by human fibroblasts. Kidney Int. 53(5), 1365–1373 (1998)

    Article  PubMed  CAS  Google Scholar 

  18. S. Kume, S. Kato, S. Yamagishi, Y. Inagaki, S. Ueda, N. Arima et al., Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J. Bone Miner. Res. 20(9), 1647–1658 (2005)

    Article  PubMed  CAS  Google Scholar 

  19. K. Abeyama, D.M. Stern, Y. Ito, K. Kawahara, Y. Yoshimoto, M. Tanaka et al., The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J. Clin. Invest. 115(5), 1267–1274 (2005)

    PubMed  CAS  Google Scholar 

  20. K.M. Myint, Y. Yamamoto, T. Doi, I. Kato, A. Harashima, H. Yonekura et al., RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin. Diabetes 55(9), 2510–2522 (2006)

    Article  PubMed  CAS  Google Scholar 

  21. A.M. Parfitt, M.K. Drezner, F.H. Glorieux, J.A. Kanis, H. Malluche, P.J. Meunier et al., Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee. J. Bone Miner. Res. 2(6), 595–610 (1987)

    Article  PubMed  CAS  Google Scholar 

  22. Z. Zhou, D. Immel, C.X. Xi, A. Bierhaus, X. Feng, L. Mei et al., Regulation of osteoclast function and bone mass by RAGE. J. Exp. Med. 203(4), 1067–1080 (2006)

    Article  PubMed  CAS  Google Scholar 

  23. B.K. Philip, P.J. Childress, A.G. Robling, A. Heller, P.P. Nawroth, A. Bierhaus et al., RAGE supports parathyroid hormone-induced gains in femoral trabecular bone. Am. J. Physiol. Endocrinol. Metab. 298(3), 714–725 (2010)

    Article  CAS  Google Scholar 

  24. T. Kislinger, C. Fu, B. Huber, W. Qu, A. Taguchi, S. Du Yan et al., N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J. Biol. Chem. 274(44), 31740–31749 (1999)

    Article  PubMed  CAS  Google Scholar 

  25. O. Hori, J. Brett, T. Slattery, R. Cao, J. Zhang, J.X. Chen et al., 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(43), 25752–25761 (1995)

    Article  PubMed  CAS  Google Scholar 

  26. A. Taguchi, D.C. Blood, G. del Toro, A. Canet, D.C. Lee, W. Qu et al., Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405(6784), 354–360 (2000)

    Article  PubMed  CAS  Google Scholar 

  27. M.A. Hofmann, S. Drury, C. Fu, W. Qu, A. Taguchi, Y. Lu et al., RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97(7), 889–901 (1999)

    Article  PubMed  CAS  Google Scholar 

  28. S.D. Yan, X. Chen, J. Fu, M. Chen, H. Zhu, A. Roher et al., RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382(6593), 685–691 (1996)

    Article  PubMed  CAS  Google Scholar 

  29. T. Chavakis, A. Bierhaus, N. Al-Fakhri, D. Schneider, S. Witte, T. Linn et al., The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J. Exp. Med. 198(10), 1507–1515 (2003)

    Article  PubMed  CAS  Google Scholar 

  30. L.G. Bucciarelli, T. Wendt, L. Rong, E. Lalla, M.A. Hofmann, M.T. Goova et al., RAGE is a multiligand receptor of the immunoglobulin superfamily: implications for homeostasis and chronic disease. Cell. Mol. Life Sci. 59(7), 1117–1128 (2002)

    Article  PubMed  CAS  Google Scholar 

  31. A.M. Schmidt, S.D. Yan, J.L. Wautier, D. Stern, Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ. Res. 84(5), 489–497 (1999)

    PubMed  CAS  Google Scholar 

  32. H. Yonekura, Y. Yamamoto, S. Sakurai, R.G. Petrova, M.J. Abedin, H. Li et al., 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, 1097–1109 (2003)

    Article  PubMed  CAS  Google Scholar 

  33. C. Schlueter, S. Hauke, A.M. Flohr, P. Rogalla, J. Bullerdiek, Tissue-specific expression patterns of the RAGE receptor and its soluble forms—a result of regulated alternative splicing? Biochim. Biophys. Acta 1630(1), 1–6 (2003)

    PubMed  CAS  Google Scholar 

  34. Q. Ding, J.N. Keller, Splice variants of the receptor for advanced glycosylation end products (RAGE) in human brain. Neurosci. Lett. 373(1), 67–72 (2005)

    Article  PubMed  CAS  Google Scholar 

  35. A. Bierhaus, P.M. Humpert, M. Morcos, T. Wendt, T. Chavakis, B. Arnold et al., Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. 83(11), 876–886 (2005)

    Article  PubMed  CAS  Google Scholar 

  36. E. Lalla, I.B. Lamster, M. Feit, L. Huang, A. Spessot, W. Qu et al., Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice. J. Clin. Invest. 105(8), 1117–1124 (2000)

    Article  PubMed  CAS  Google Scholar 

  37. J.L. Wautier, C. Zoukourian, O. Chappey, M.P. Wautier, P.J. Guillausseau, R. Cao et al., Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J. Clin. Invest. 97(1), 238–243 (1996)

    Article  PubMed  CAS  Google Scholar 

  38. L. Park, K.G. Raman, K.J. Lee, Y. Lu, L.J. Ferran Jr., W.S. Chow et al., Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat. Med. 4(9), 1025–1031 (1998)

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study is supported in part by a grant from the Kidney Foundation of Japan (JKFB09-16; YH), and Grant-in-Aid for Young Scientists (B) (22790790; YH) and the 21st Century COE Program “Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as Model” (MF and SK) by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. We are grateful to Kureha Special Laboratory Co. Ltd. for technical assistance. We also thank S. Matsuda and R. Sadato (Kobe University School of Medicine) for their technical assistance.

Author information

Authors and Affiliations

  1. Division of Nephrology and Kidney Center, Kobe University School of Medicine, Kobe, Japan

    Yasuhiro Hamada, Keiji Kono, Shunsuke Goto, Hirotaka Komaba, Hideki Fujii & Masafumi Fukagawa

  2. Department of Nutrition, Kobe University Hospital, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Yasuhiro Hamada & Makoto Usami

  3. Division of Diagnostic Molecular Pathology, Kobe University Graduate School of Medicine, Kobe, Japan

    Sohei Kitazawa & Riko Kitazawa

  4. Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

    Yasuhiko Yamamoto & Hiroshi Yamamoto

  5. Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan

    Masafumi Fukagawa

Authors
  1. Yasuhiro Hamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sohei Kitazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Riko Kitazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keiji Kono
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shunsuke Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hirotaka Komaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hideki Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasuhiko Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroshi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Makoto Usami
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Masafumi Fukagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhiro Hamada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hamada, Y., Kitazawa, S., Kitazawa, R. et al. The effects of the receptor for advanced glycation end products (RAGE) on bone metabolism under physiological and diabetic conditions. Endocr 38, 369–376 (2010). https://doi.org/10.1007/s12020-010-9390-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-010-9390-9

Keywords

Search

Navigation