Current Osteoporosis Reports

, Volume 17, Issue 1, pp 16–25 | Cite as

RAGE Signaling in Skeletal Biology

  • Lilian I. PlotkinEmail author
  • Alyson L. Essex
  • Hannah M. Davis
Skeletal Biology and Regulation (M Forwood and A Robling, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Skeletal Biology and Regulation


Purpose of Review

The receptor for advanced glycation end products (RAGE) and several of its ligands have been implicated in the onset and progression of pathologies associated with aging, chronic inflammation, and cellular stress. In particular, the role of RAGE and its ligands in bone tissue during both physiological and pathological conditions has been investigated. However, the extent to which RAGE signaling regulates bone homeostasis and disease onset remains unclear. Further, RAGE effects in the different bone cells and whether these effects are cell-type specific is unknown. The objective of the current review is to describe the literature over RAGE signaling in skeletal biology as well as discuss the clinical potential of RAGE as a diagnostic and/or therapeutic target in bone disease.

Recent Findings

The role of RAGE and its ligands during skeletal homeostasis, tissue repair, and disease onset/progression is beginning to be uncovered. For example, detrimental effects of the RAGE ligands, advanced glycation end products (AGEs), have been identified for osteoblast viability/activity, while others have observed that low level AGE exposure stimulates osteoblast autophagy, which subsequently promotes viability and function. Similar findings have been reported with HMGB1, another RAGE ligand, in which high levels of the ligand are associated with osteoblast/osteocyte apoptosis, whereas low level/short-term administration stimulates osteoblast differentiation/bone formation and promotes fracture healing. Additionally, elevated levels of several RAGE ligands (AGEs, HMGB1, S100 proteins) induce osteoblast/osteocyte apoptosis and stimulate cytokine production, which is associated with increased osteoclast differentiation/activity. Conversely, direct RAGE-ligand exposure in osteoclasts may have inhibitory effects. These observations support a conclusion that elevated bone resorption observed in conditions of high circulating ligands and RAGE expression are due to actions on osteoblasts/osteocytes rather than direct actions on osteoclasts, although additional work is required to substantiate the observations.


Recent studies have demonstrated that RAGE and its ligands play an important physiological role in the regulation of skeletal development, homeostasis, and repair/regeneration. Conversely, elevated levels of RAGE and its ligands are clearly related with various diseases associated with increased bone loss and fragility. However, despite the recent advancements in the field, many questions regarding RAGE and its ligands in skeletal biology remain unanswered.


RAGE Bone Osteoblast Osteoclast Osteocyte Osteoporosis 


Funding Information

This research was supported by the National Institutes of Health R01-AR067210 to LIP. HMD is supported by an NIH T32-AR065971 grant and by the 2018 Cagiantas Scholarship from the Indiana University School of Medicine. ALE is supported by an NIH T32-AR065971 grant.

Compliance with Ethical Standards

Conflict of Interest

Lillian Plotkin, Alyson Essex, and Hannah Davis declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Sorci G, Riuzzi F, Giambanco I, Donato R. RAGE in tissue homeostasis, repair and regeneration. Biochim Biophys Acta. 2013;1833:101–9.CrossRefGoogle Scholar
  2. 2.
    Lee EJ, Park JH. Receptor for advanced glycation endproducts (RAGE), its ligands, and soluble RAGE: potential biomarkers for diagnosis and therapeutic targets for human renal diseases. Genomics Inform. 2013;11:224–9.CrossRefGoogle Scholar
  3. 3.
    Hudson BI, Lippman ME. Targeting RAGE signaling in inflammatory disease. Annu Rev Med. 2018;69:349–64.CrossRefGoogle Scholar
  4. 4.
    Zhou Z, Xiong WC. RAGE and its ligands in bone metabolism. Front Biosci (Schol Ed). 2011;3:768–76.Google Scholar
  5. 5.
    Ray R, Juranek JK, Rai V. RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci Biobehav Rev. 2016;62:48–55.CrossRefGoogle Scholar
  6. 6.
    Hofer S, Uhle F, Fleming T, Hell C, Schmoch T, Bruckner T, et al. RAGE-mediated inflammation in patients with septic shock. J Surg Res. 2016;202:315–27.CrossRefGoogle Scholar
  7. 7.
    Lutterloh EC, Opal SM, Pittman DD, Keith JC Jr, Tan XY, Clancy BM, et al. Inhibition of the RAGE products increases survival in experimental models of severe sepsis and systemic infection. Crit Care. 2007;11:R122.CrossRefGoogle Scholar
  8. 8.
    Rojas A, Morales M, Gonzalez I, Araya P. Inhibition of RAGE axis signaling: a pharmacological challenge. Curr Drug Targets. 2018.
  9. 9.
    Jung ES, Chung W, Kim AJ, Ro H, Chang JH, Lee HH, et al. Associations between soluble receptor for advanced glycation end products (sRAGE) and S100A12 (EN-RAGE) with mortality in long-term hemodialysis patients. J Korean Med Sci. 2017;32:54–9.CrossRefGoogle Scholar
  10. 10.
    Galliera E, Marazzi MG, Vianello E, Drago L, Luzzati A, Bendinelli P, et al. Circulating sRAGE in the diagnosis of osteolytic bone metastasis. J Biol Regul Homeost Agents. 2016;30:1203–8.Google Scholar
  11. 11.
    White DL, Hoogeveen RC, Chen L, Richardson P, Ravishankar M, Shah P, et al. A prospective study of soluble receptor for advanced glycation end products and adipokines in association with pancreatic cancer in postmenopausal women. Cancer Med. 2018;7:2180–91.CrossRefGoogle Scholar
  12. 12.
    Maillard-Lefebvre H, Boulanger E, Daroux M, Gaxatte C, Hudson BI, Lambert M. Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases. Rheumatology (Oxford). 2009;48:1190–6.CrossRefGoogle Scholar
  13. 13.
    Hudson BI, Kalea AZ, Del Mar Arriero M, Harja E, Boulanger E, D'Agati V, et al. Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem. 2008;283:34457–68.CrossRefGoogle Scholar
  14. 14.
    Hudson BI, Carter AM, Harja E, Kalea AZ, Arriero M, Yang H, et al. Identification, classification, and expression of RAGE gene splice variants. FASEB J. 2008;22:1572–80.CrossRefGoogle Scholar
  15. 15.
    Kalea AZ, Reiniger N, Yang H, Arriero M, Schmidt AM, Hudson BI. Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene. FASEB J. 2009;23:1766–74.CrossRefGoogle Scholar
  16. 16.
    Jules J, Maiguel D, Hudson BI. Alternative splicing of the RAGE cytoplasmic domain regulates cell signaling and function. PLoS One. 2013;8:e78267.CrossRefGoogle Scholar
  17. 17.
    Hanford LE, Enghild JJ, Valnickova Z, Petersen SV, Schaefer LM, Schaefer TM, et al. Purification and characterization of mouse soluble receptor for advanced glycation end products (sRAGE). J Biol Chem. 2004;279:50019–24.CrossRefGoogle Scholar
  18. 18.
    Braley A, Kwak T, Jules J, Harja E, Landgraf R, Hudson BI. Regulation of receptor for advanced glycation end products (RAGE) Ectodomain shedding and its role in cell function. J Biol Chem. 2016;291:12057–73.CrossRefGoogle Scholar
  19. 19.
    Chuah YK, Basir R, Talib H, Tie TH, Nordin N. Receptor for advanced glycation end products and its involvement in inflammatory diseases. Int J Inflam. 2013;2013:403460.CrossRefGoogle Scholar
  20. 20.
    Juranek JK, Daffu GK, Geddis MS, Li H, Rosario R, Kaplan BJ, et al. Soluble RAGE treatment delays progression of amyotrophic lateral sclerosis in SOD1 mice. Front Cell Neurosci. 2016;10:117.CrossRefGoogle Scholar
  21. 21.
    Oh S, Son M, Choi J, Lee S, Byun K. sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer’s disease model. Biochem Biophys Res Commun. 2018;495:807–13.CrossRefGoogle Scholar
  22. 22.
    Antonelli A, Di Maggio S, Rejman J, Sanvito F, Rossi A, Catucci A, et al. The shedding-derived soluble receptor for advanced glycation endproducts sustains inflammation during acute Pseudomonas aeruginosa lung infection. Biochim Biophys Acta. 2017;1861:354–64.CrossRefGoogle Scholar
  23. 23.
    Brisslert M, Amu S, Pullerits R. Intra-peritoneal sRAGE treatment induces alterations in cellular distribution of CD19(+), CD3 (+) and Mac-1 (+) cells in lymphoid organs and peritoneal cavity. Cell Tissue Res. 2013;351:139–48.CrossRefGoogle Scholar
  24. 24.
    Rai V, Maldonado AY, Burz DS, Reverdatto S, Schmidt AM, Shekhtman A. Signal transduction in RAGE: solution structure of C-terminal RAGE (ctRAGE) and its binding to mDia1. J Biol Chem. 2011.Google Scholar
  25. 25.
    Yang H, Lundback P, Ottosson L, Erlandsson-Harris H, Venereau E, Bianchi ME, et al. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol Med. 2012;18:250–9.CrossRefGoogle Scholar
  26. 26.
    Bongarzone S, Savickas V, Luzi F, Gee AD. Targeting the receptor for advanced glycation endproducts (RAGE): a medicinal chemistry perspective. J Med Chem. 2017;60:7213–32.CrossRefGoogle Scholar
  27. 27.
    Zhou Z, Immel D, Xi CX, Bierhaus A, Feng X, Mei L, et al. Regulation of osteoclast function and bone mass by RAGE. J Exp Med. 2006;203:1067–80.CrossRefGoogle Scholar
  28. 28.
    Ito Y, Teitelbaum SL, Zou W, Zheng Y, Johnson JF, Chappel J, et al. Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization. J Clin Invest. 2010;120:1981–1993.Google Scholar
  29. 29.
    •• Meng HZ, Zhang WL, Liu F, Yang MW. Advanced glycation end products affect osteoblast proliferation and function by modulating autophagy via the receptor of advanced glycation end products/Raf protein/mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase (RAGE/Raf/MEK/ERK) pathway. J Biol Chem. 2015;290:28189–99. This study demonstrated that low levels of AGE-RAGE signaling stimulates autophagy and enhances osteoblast viability. CrossRefGoogle Scholar
  30. 30.
    Schmidt AM, Yan SD, Yan SF, Stern DM. The biology of the receptor for advanced glycation end products and its ligands. Biochim Biophys Acta. 2000;1498:99–111.CrossRefGoogle Scholar
  31. 31.
    Bidwell JP, Yang J, Robling AG. Is HMGB1 an osteocyte alarmin? J. Cell Biochem. 2008;103:1671–80.CrossRefGoogle Scholar
  32. 32.
    Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl). 2005;83:876–86.CrossRefGoogle Scholar
  33. 33.
    Ramasamy R, Shekhtman A, Schmidt AM. The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease. Expert Opin Ther Targets. 2016;20:431–46.CrossRefGoogle Scholar
  34. 34.
    Byun K, Yoo Y, Son M, Lee J, Jeong GB, Park YM, et al. Advanced glycation end-products produced systemically and by macrophages: a common contributor to inflammation and degenerative diseases. Pharmacol Ther. 2017;177:44–55.CrossRefGoogle Scholar
  35. 35.
    Poundarik AA, Wu PC, Evis Z, Sroga GE, Ural A, Rubin M, et al. A direct role of collagen glycation in bone fracture. J Mech Behav Biomed Mater. 2015;52:120–30.CrossRefGoogle Scholar
  36. 36.
    Rubin MR, Paschalis EP, Poundarik A, Sroga GE, McMahon DJ, Gamsjaeger S, et al. Advanced glycation endproducts and bone material properties in type 1 diabetic mice. PLoS One. 2016;11:e0154700.CrossRefGoogle Scholar
  37. 37.
    Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–5.CrossRefGoogle Scholar
  38. 38.
    Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, et al. High mobility group box 1 protein interacts with multiple toll-like receptors. Am J Physiol Cell Physiol. 2006;290:C917–24.CrossRefGoogle Scholar
  39. 39.
    Palumbo R, Sampaolesi M, De Marchis F, Tonlorenzi R, Colombetti S, Mondino A, et al. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol. 2004;164:441–9.CrossRefGoogle Scholar
  40. 40.
    Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ. HMG-1 as a mediator of acute lung inflammation. J Immunol (Baltimore, Md. : 1950). 2000;165:2950–4.CrossRefGoogle Scholar
  41. 41.
    Charoonpatrapong K, Shah R, Robling AG, Alvarez M, Clapp DW, Chen S, et al. HMGB1 expression and release by bone cells. J Cell Physiol. 2006;207:480–90.CrossRefGoogle Scholar
  42. 42.
    Hou C, Luan L, Ren C. Oxidized low-density lipoprotein promotes osteoclast differentiation from CD68 positive mononuclear cells by regulating HMGB1 release. Biochem Biophys Res Commun. 2018;495:1356–62.CrossRefGoogle Scholar
  43. 43.
    Marenholz I, Heizmann CW, Fritz G. S100 proteins in mouse and man: from evolution to function and pathology (including an update of the nomenclature). Biochem Biophys Res Commun. 2004;322:1111–22.CrossRefGoogle Scholar
  44. 44.
    Ostendorp T, Leclerc E, Galichet A, Koch M, Demling N, Weigle B, et al. Structural and functional insights into RAGE activation by multimeric S100B. EMBO J. 2007;26:3868–78.CrossRefGoogle Scholar
  45. 45.
    Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97:889–901.CrossRefGoogle Scholar
  46. 46.
    Riuzzi F, Sorci G, Beccafico S, Donato R. S100B engages RAGE or bFGF/FGFR1 in myoblasts depending on its own concentration and myoblast density. Implications for muscle regeneration. PloS one. 2012;7:e28700.CrossRefGoogle Scholar
  47. 47.
    Yoshida T, Flegler A, Kozlov A, Stern PH. Direct inhibitory and indirect stimulatory effects of RAGE ligand S100 on sRANKL-induced osteoclastogenesis. J Cell Biochem. 2009;107:917–25.CrossRefGoogle Scholar
  48. 48.
    Kim H, Lee YD, Kim MK, Kwon JO, Song MK, Lee ZH, et al. Extracellular S100A4 negatively regulates osteoblast function by activating the NF-kappaB pathway. BMB Rep. 2017;50:97–102.CrossRefGoogle Scholar
  49. 49.
    McLeod J, Curtis N, Lewis HD, Good MA, Fagan MJ, Genever PG. Gamma-secretase-dependent cleavage of amyloid precursor protein regulates osteoblast behavior. FASEB J. 2009;23:2942–55.CrossRefGoogle Scholar
  50. 50.
    Dawkins E, Small DH. Insights into the physiological function of the β-amyloid precursor protein: beyond Alzheimer’s disease. J Neurochem. 2014;129:756–69.CrossRefGoogle Scholar
  51. 51.
    Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, et al. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009;106:20021–6.CrossRefGoogle Scholar
  52. 52.
    Li S, Yang B, Teguh D, Zhou L, Xu J, Rong L. Amyloid beta peptide enhances RANKL-induced osteoclast activation through NF-kappaB, ERK, and calcium oscillation signaling. Int J Mol Sci. 2016;17.Google Scholar
  53. 53.
    Cui S, Xiong F, Hong Y, Jung JU, Li XS, Liu JZ, et al. APPswe/Abeta regulation of osteoclast activation and RAGE expression in an age-dependent manner. J Bone Miner Res. 2011;26:1084–98.CrossRefGoogle Scholar
  54. 54.
    Li S, Liu B, Zhang L, Rong L. Amyloid beta peptide is elevated in osteoporotic bone tissues and enhances osteoclast function. Bone. 2014;61:164–75.CrossRefGoogle Scholar
  55. 55.
    Xia WF, Jung JU, Shun C, Xiong S, Xiong L, Shi XM, et al. Swedish mutant APP suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine. J Bone Miner Res. 2013;28:2122–35.CrossRefGoogle Scholar
  56. 56.
    Zhao L, Liu S, Wang Y, Zhang Q, Zhao W, Wang Z, et al. Effects of curculigoside on memory impairment and bone loss via anti-oxidative character in APP/PS1 mutated transgenic mice. PLoS One. 2015;10:e0133289.CrossRefGoogle Scholar
  57. 57.
    Philip BK, Childress PJ, Robling AG, Heller A, Nawroth PP, Bierhaus A, et al. RAGE supports parathyroid hormone-induced gains in femoral trabecular bone. Am J Physiol Endocrinol Metab. 2010;298:E714–25.CrossRefGoogle Scholar
  58. 58.
    Ding KH, Wang ZZ, Hamrick MW, Deng ZB, Zhou L, Kang B, et al. Disordered osteoclast formation in RAGE-deficient mouse establishes an essential role for RAGE in diabetes related bone loss. Biochem Biophys Res Commun. 2006;340:1091–7.CrossRefGoogle Scholar
  59. 59.
    Zhou Z, Han JY, Xi CX, Xie JX, Feng X, Wang CY, et al. HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J Bone Miner Res. 2008;23:1084–96.CrossRefGoogle Scholar
  60. 60.
    Biswas S, Duttenhoefer F, Li H, Matte D, Igwe JC, Humpert PM, Kasperk C, Nawroth PP, Bierhaus A. RAGE deficiency induces a proinflammatory phenotype in bones and osteoblasts through PPAR-a suppression. 2008;3.Google Scholar
  61. 61.
    Aoyagi H, Yamashiro K, Hirata-Yoshihara C, Ideguchi H, Yamasaki M, Kawamura M, et al. HMGB1-induced inflammatory response promotes bone healing in murine tooth extraction socket. J Cell Biochem. 2018;119:5481–90.CrossRefGoogle Scholar
  62. 62.
    Feng L, Xue D, Chen E, Zhang W, Gao X, Yu J, et al. HMGB1 promotes the secretion of multiple cytokines and potentiates the osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signaling pathway. Exp Ther Med. 2016;12:3941–7.CrossRefGoogle Scholar
  63. 63.
    Hurtgen BJ, Ward CL, Leopold Wager CM, Garg K, Goldman SM, Henderson BEP, McKinley TO, Greising SM, Wenke JC, Corona BT. Autologous minced muscle grafts improve endogenous fracture healing and muscle strength after musculoskeletal trauma. Physiol Rep. 2017;5.Google Scholar
  64. 64.
    Taniguchi N, Yoshida K, Ito T, Tsuda M, Mishima Y, Furumatsu T, et al. Stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification. Mol. Cell Biol. 2007;27:5650–63.Google Scholar
  65. 65.
    Li Q, Yu B, Yang P. Hypoxia-induced HMGB1 in would tissues promotes the osteoblast cell proliferation via activating ERK/JNK signaling. Int J Clin Exp Med. 2015;8:15087–97.Google Scholar
  66. 66.
    Franke S, Ruster C, Pester J, Hofmann G, Oelzner P, Wolf G. Advanced glycation end products affect growth and function of osteoblasts. Clin Exp Rheumatol. 2011;29:650–60.Google Scholar
  67. 67.
    Kume S, Kato S, Yamagishi S, Inagaki Y, Ueda S, Arima N, 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. 2005;20:1647–58.CrossRefGoogle Scholar
  68. 68.
    Aikawa E, Fujita R, Asai M, Kaneda Y, Tamai K. Receptor for advanced glycation end products-mediated signaling impairs the maintenance of bone marrow mesenchymal stromal cells in diabetic model mice. Stem Cells Dev. 2016;25:1721–32.CrossRefGoogle Scholar
  69. 69.
    Alikhani M, Alikhani Z, Boyd C, MacLellan CM, Raptis M, Liu R, et al. Advanced glycation endproducts stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways. Bone. 2007;40:345–53.CrossRefGoogle Scholar
  70. 70.
    • Liu J, Mao J, Jiang Y, Xia L, Mao L, Wu Y, et al. AGEs induce apoptosis in rat osteoblast cells by activating the caspase-3 signaling pathway under a high-glucose environment in vitro. Appl Biochem Biotechnol. 2016;178:1015–27. The studies in this article showed that in rat osteoblastic cells, high-glucose levels lead to AGE accumulation, which subsequently activates caspase-3 and increased apoptosis. CrossRefGoogle Scholar
  71. 71.
    •• Mao YX, Cai WJ, Sun XY, Dai PP, Li XM, Wang Q, et al. RAGE-dependent mitochondria pathway: a novel target of silibinin against apoptosis of osteoblastic cells induced by advanced glycation end products. Cell Death Dis. 2018;9:674. This study provided a new insight into the mitochondrial mechanisms that lead to AGE-induced osteoblastic cell apoptosis and identified a potential clinical use of silibinin for the prevention or treatment of diabetic osteoporosis. CrossRefGoogle Scholar
  72. 72.
    McCarthy AD, Etcheverry SB, Bruzzone L, Lettieri G, Barrio DA, Cortizo AM. Non-enzymatic glycosylation of a type I collagen matrix: effects on osteoblastic development and oxidative stress. BMC Cell Biol. 2001;2:16.CrossRefGoogle Scholar
  73. 73.
    Cortizo AM, Lettieri MG, Barrio DA, Mercer N, Etcheverry SB, McCarthy AD. Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). Mol Cell Biochem. 2003;250:1–10.CrossRefGoogle Scholar
  74. 74.
    Aoki C, Uto K, Honda K, Kato Y, Oda H. Advanced glycation end products suppress lysyl oxidase and induce bone collagen degradation in a rat model of renal osteodystrophy. Lab Investig. 2013;93:1170–83.CrossRefGoogle Scholar
  75. 75.
    Khosravi R, Sodek KL, Faibish M, Trackman PC. Collagen advanced glycation inhibits its discoidin domain receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts. Bone. 2014;58:33–41.CrossRefGoogle Scholar
  76. 76.
    Notsu M, Kanazawa I, Takeno A, Yokomoto-Umakoshi M, Tanaka KI, Yamaguchi T, et al. Advanced glycation end product 3 (AGE3) increases apoptosis and the expression of sclerostin by stimulating TGF-beta expression and secretion in osteocyte-like MLO-Y4-A2 cells. Calcif Tissue Int. 2017;100:402–11.CrossRefGoogle Scholar
  77. 77.
    •• Chen H, Liu W, Wu X, Gou M, Shen J, Wang H. Advanced glycation end products induced IL-6 and VEGF-A production and apoptosis in osteocyte-like MLO-Y4 cells by activating RAGE and ERK1/2, P38 and STAT3 signalling pathways. Int Immunopharmacol. 2017;52:143–9. This article provided evidence showing that AGEs can activate the ERK1/2, P38 and STAT3 pathways via RAGE. Additionally, AGE-induced activation of these pathways stimulates IL-6 and VEGF-A production and osteocyte apoptosis. CrossRefGoogle Scholar
  78. 78.
    Tanaka K, Yamaguchi T, Kanazawa I, Sugimoto T. Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun. 2015;461:193–9.CrossRefGoogle Scholar
  79. 79.
    Yang J, Shah R, Robling AG, Templeton E, Yang H, Tracey KJ, et al. HMGB1 is a bone-active cytokine. J. Cell Physiol. 2008;214:730–9.CrossRefGoogle Scholar
  80. 80.
    •• Davis HM, Pacheco-Costa R, Atkinson EG, Brun LR, Gortazar AR, Harris J, et al. Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging. Aging Cell. 2017;16:551–63. This article showed that Cx43 and miR21 are required to maintain osteocyte survival and identified RANKL and HMGB1 as two molecules involved with elevated osteoclastogenesis. CrossRefGoogle Scholar
  81. 81.
    • Li Z, Li C, Zhou Y, Chen W, Luo G, Zhang Z, et al. Advanced glycation end products biphasically modulate bone resorption in osteoclast-like cells. Am J Physiol Endocrinol Metab. 2016;310:E355–66. This article demonstrated that AGEs biphasically modulate osteoclast activity in a differentiation stage-dependent manner. CrossRefGoogle Scholar
  82. 82.
    Dong XN, Qin A, Xu J, Wang X. In situ accumulation of advanced glycation endproducts (AGEs) in bone matrix and its correlation with osteoclastic bone resorption. Bone. 2011;49:174–83.CrossRefGoogle Scholar
  83. 83.
    Santana RB, Xu L, Chase HB, Amar S, Graves DT, Trackman PC. A role for advanced glycation end products in diminished bone healing in type 1 diabetes. Diabetes. 2003;52:1502–10.CrossRefGoogle Scholar
  84. 84.
    Raska I Jr, Raskova M, Zikan V, Skrha J. Prevalence and risk factors of osteoporosis in postmenopausal women with type 2 diabetes mellitus. Cent Eur J Public Health. 2017;25:3–10.CrossRefGoogle Scholar
  85. 85.
    Yamamoto M, Yamaguchi T, Yamauchi M, Sugimoto T. Low serum level of the endogenous secretory receptor for advanced glycation end products (esRAGE) is a risk factor for prevalent vertebral fractures independent of bone mineral density in patients with type 2 diabetes. Diabetes Care. 2009;32:2263–8.CrossRefGoogle Scholar
  86. 86.
    Myles A, Viswanath V, Singh YP, Aggarwal A. Soluble receptor for advanced glycation endproducts is decreased in patients with juvenile idiopathic arthritis (ERA category) and inversely correlates with disease activity and S100A12 levels. J Rheumatol. 2011;38:1994–9.CrossRefGoogle Scholar
  87. 87.
    Pullerits R, d'Elia HF, Tarkowski A, Carlsten H. The decrease of soluble RAGE levels in rheumatoid arthritis patients following hormone replacement therapy is associated with increased bone mineral density and diminished bone/cartilage turnover: a randomized controlled trial. Rheumatology (Oxford). 2009;48:785–90.CrossRefGoogle Scholar
  88. 88.
    Lamb LS, Alfonso H, Norman PE, Davis TME, Forbes J, Muench G, et al. Advanced glycation end products and esRAGE are associated with bone turnover and incidence of hip fracture in older men. J Clin Endocrinol Metab. 2018;103:4224–31.CrossRefGoogle Scholar
  89. 89.
    •• Galliera E, Marazzi MG, Gazzaruso C, Gallotti P, Coppola A, Montalcini T, et al. Evaluation of circulating sRAGE in osteoporosis according to BMI, adipokines and fracture risk: a pilot observational study. Immun Ageing. 2017;14:13. This article found that serum sRAGE is associated with bone fragility, as well as, with BMI and leptin levels. These findings demonstrate the diagnostic potential sRAGE not only as a marker of osteoporosis, but also lipid metabolism status. CrossRefGoogle Scholar
  90. 90.
    Lalla E, Lamster IB, Feit M, Huang L, Spessot A, Qu W, et al. Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice. J Clin Invest. 2000;105:1117–24.CrossRefGoogle Scholar
  91. 91.
    Deane RJ. Is RAGE still a therapeutic target for Alzheimer’s disease? Future Med Chem. 2012;4:915–25.CrossRefGoogle Scholar
  92. 92.
    Wang J, Wang H, Shi J, Ding Y. Effects of bone marrow MSCs transfected with sRAGE on the intervention of HMGB1 induced immuno-inflammatory reaction. Int J Clin Exp Pathol. 2015;8:12028–40.Google Scholar
  93. 93.
    Walker D, Lue LF, Paul G, Patel A, Sabbagh MN. Receptor for advanced glycation endproduct modulators: a new therapeutic target in Alzheimer’s disease. Expert Opin Investig Drugs. 2015;24:393–9.CrossRefGoogle Scholar
  94. 94.
    Panza F, Seripa D, Solfrizzi V, Imbimbo BP, Lozupone M, Leo A, et al. Emerging drugs to reduce abnormal beta-amyloid protein in Alzheimer’s disease patients. Expert Opin Emerg Drugs. 2016;21:377–91.CrossRefGoogle Scholar
  95. 95.
    Galasko D, Bell J, Mancuso JY, Kupiec JW, Sabbagh MN, van Dyck C, et al. Clinical trial of an inhibitor of RAGE-Abeta interactions in Alzheimer disease. Neurology. 2014;82:1536–42.CrossRefGoogle Scholar
  96. 96.
    Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, et al. A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012;122:1377–92.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Lilian I. Plotkin
    • 1
    • 2
    • 3
    Email author
  • Alyson L. Essex
    • 1
    • 3
  • Hannah M. Davis
    • 1
    • 3
  1. 1.Department of Anatomy and Cell BiologyIndiana University School of MedicineIndianapolisUSA
  2. 2.Roudebush Veterans Administration Medical CenterIndianapolisUSA
  3. 3.Indiana Center for Musculoskeletal HealthIndianapolisUSA

Personalised recommendations