Calcified Tissue International

, Volume 102, Issue 5, pp 522–532 | Cite as

The Role of Autoantibodies in Bone Metabolism and Bone Loss

  • Barbara Hauser
  • Ulrike Harre


Many autoimmune diseases are associated with deranged bone metabolism. The resulting localized or systemic bone loss can compromise the quality of life of patients by causing local bone deformities or fragility fractures. There is emerging evidence that antibodies have a direct impact on key players of bone homeostasis, in particular osteoclasts. Clinical and pre-clinical studies provide insight into the function of autoantibodies related to Rheumatoid Arthritis (rheumatoid factor, anti-citrullinated protein antibodies, and anti-carbamylated protein antibodies) and their inflammation-independent interaction with bone cells. Furthermore, we summarize the current knowledge about neutralizing antibodies to the antiresorptive protein osteoprotegerin, which have been described in patients with Coeliac Disease, Rheumatoid Arthritis, and Spondyloarthritis.


Autoantibodies Bone loss Rheumatoid arthritis Osteoprotegerin ACPA Osteoclast 



BH is supported by an Arthritis Research UK Clinical PhD studentship award. UH is supported by the Deutsche Forschungsgemeinschaft, IMI-BTCure, and the Elsbeth-Bonhoff Stiftung.

Conflict of interest

Barbara Hauser and Ulrike Harre declare that they have no conflicts of interest.


  1. 1.
    Rosen C, Bouillon R, Compston JE, Rosen V (2013) Primer on the metabolic bone diseases and disorders of mineral metabolism. 8th edn, Wiley, HobokenCrossRefGoogle Scholar
  2. 2.
    Redlich K, Smolen JS (2012) Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov 11 234–250CrossRefGoogle Scholar
  3. 3.
    Bultink IE, Vis M, van der Horst-Bruinsma IE, Lems WF (2012) Inflammatory rheumatic disorders and bone. Curr Rheumatol Rep 14:224–230CrossRefGoogle Scholar
  4. 4.
    Bianchi ML, Bardella MT (2002) Bone and celiac disease. Calcif Tissue Int 71:465–471CrossRefGoogle Scholar
  5. 5.
    Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM (2015) The generation of antibody-secreting plasma cells. Nat Rev Immunol 15:160–171CrossRefGoogle Scholar
  6. 6.
    Brian R, Walker NRC, Stuart H, Ralston, Penman I (2014) Davidson’s principles and practice of medicine. 22 edn Elsevier, AmsterdamGoogle Scholar
  7. 7.
    Smolen JS, Steiner G (1998) Are autoantibodies active players or epiphenomena? Curr Opin Rheumatol 10:201–206CrossRefGoogle Scholar
  8. 8.
    McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219CrossRefGoogle Scholar
  9. 9.
    Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK (2000) Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register. Arthritis Rheum 43:522–530Google Scholar
  10. 10.
    Hauser B, Riches PL, Wilson JF, Horne AE, Ralston SH (2014) Prevalence and clinical prediction of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis. Rheumatology 53:1759–1766CrossRefGoogle Scholar
  11. 11.
    van Staa TP, Geusens P, Bijlsma JW, Leufkens HG, Cooper C (2006) Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum 54:3104–3112CrossRefGoogle Scholar
  12. 12.
    Tak PP, Rigby WF, Rubbert-Roth A, Peterfy CG, van Vollenhoven RF, Stohl W, Hessey E, Chen A, Tyrrell H, Shaw TM (2011) Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis 70:39–46Google Scholar
  13. 13.
    Ambarus C, Yeremenko N, Tak PP, Baeten D (2012) Pathogenesis of spondyloarthritis: autoimmune or autoinflammatory? Curr Opin Rheumatol 24:351–358CrossRefGoogle Scholar
  14. 14.
    Baerlecken NT, Nothdorft S, Stummvoll GH, Sieper J, Rudwaleit M, Reuter S, Matthias T, Schmidt RE, Witte T (2014) Autoantibodies against CD74 in spondyloarthritis. Ann Rheum Dis 73:1211–1214CrossRefGoogle Scholar
  15. 15.
    Tsui FW, Tsui HW, Las Heras F, Pritzker KP, Inman RD (2014) Serum levels of novel noggin and sclerostin-immune complexes are elevated in ankylosing spondylitis. Ann Rheum Dis 73:1873–1879CrossRefGoogle Scholar
  16. 16.
    Hauser B, Zhao S, Visconti MR, Riches PL, Fraser WD, Piec I, Goodson NJ, Ralston SH (2017) Autoantibodies to osteoprotegerin are associated with low hip bone mineral density and history of fractures in axial spondyloarthritis: a cross-sectional observational study. Calcif Tissue Int. PubMedCentralGoogle Scholar
  17. 17.
    Braun J, Sieper J (2007) Ankylosing spondylitis. Lancet 369:1379–1390CrossRefGoogle Scholar
  18. 18.
    Donnelly S, Doyle DV, Denton A, Rolfe I, McCloskey EV, Spector TD (1994) Bone mineral density and vertebral compression fracture rates in ankylosing spondylitis. Ann Rheum Dis 53:117–121CrossRefGoogle Scholar
  19. 19.
    Ralston SH, Urquhart GD, Brzeski M, Sturrock RD (1990) Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis. BMJ 300:563–565CrossRefGoogle Scholar
  20. 20.
    van der Weijden MA, van der Horst-Bruinsma IE, van Denderen JC, Dijkmans BA, Heymans MW, Lems WF (2012) High frequency of vertebral fractures in early spondylarthropathies. Osteoporos Int 23:1683–1690Google Scholar
  21. 21.
    Wendling D, Cedoz JP, Racadot E, Dumoulin G (2007) Serum IL-17, BMP-7, and bone turnover markers in patients with ankylosing spondylitis. Joint Bone Spine 74:304–305Google Scholar
  22. 22.
    Fasano A, Catassi C (2012) Clinical practice. Celiac disease. N Engl J Med 367:2419–2426CrossRefGoogle Scholar
  23. 23.
    Pazianas M, Butcher GP, Subhani JM, Finch PJ, Ang L, Collins C, Heaney RP, Zaidi M, Maxwell JD (2005) Calcium absorption and bone mineral density in celiacs after long term treatment with gluten-free diet and adequate calcium intake. Osteoporos Int 16:56–63CrossRefGoogle Scholar
  24. 24.
    Real A, Gilbert N, Hauser B, Kennedy N, Shand A, Gillett H, Gillett P, Goddard C, Cebolla A, Sousa C, Fraser WD, Satsangi J, Ralston SH, Riches PL (2015) Characterisation of osteoprotegerin autoantibodies in coeliac disease. Calcif Tissue Int 97:125–133CrossRefGoogle Scholar
  25. 25.
    Riches PL, McRorie E, Fraser WD, Determann C, van’t Hof R, Ralston SH (2009) Osteoporosis associated with neutralizing autoantibodies against osteoprotegerin. N Engl J Med 361:1459–1465CrossRefGoogle Scholar
  26. 26.
    Nakken B, Papp G, Bosnes V, Zeher M, Nagy G, Szodoray P (2017) Biomarkers for rheumatoid arthritis: from molecular processes to diagnostic applications-current concepts and future perspectives. Immunol Lett 189:13–18CrossRefGoogle Scholar
  27. 27.
    Baka Z, Gyorgy B, Geher P, Buzas EI, Falus A, Nagy G (2012) Citrullination under physiological and pathological conditions. Joint Bone Spine 79:431–436CrossRefGoogle Scholar
  28. 28.
    Nienhuis RL, Mandema E (1964) A new serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann Rheum Dis 23:302–305CrossRefGoogle Scholar
  29. 29.
    Sebbag M, Chapuy-Regaud S, Auger I, Petit-Texeira E, Clavel C, Nogueira L, Vincent C, Cornelis F, Roudier J, Serre G (2004) Clinical and pathophysiological significance of the autoimmune response to citrullinated proteins in rheumatoid arthritis. Joint Bone Spine 71:493–502CrossRefGoogle Scholar
  30. 30.
    Burska AN, Hunt L, Boissinot M, Strollo R, Ryan BJ, Vital E, Nissim A, Winyard PG, Emery P, Ponchel F (2014) Autoantibodies to posttranslational modifications in rheumatoid arthritis. Mediat Inflamm 2014:492873Google Scholar
  31. 31.
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69:1580–1588CrossRefGoogle Scholar
  32. 32.
    Schellekens GA, Visser H, de Jong BA, van den Hoogen FH, Hazes JM, Breedveld FC, van Venrooij WJ (2000) The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 43:155–163CrossRefGoogle Scholar
  33. 33.
    Jilani AA, Mackworth-Young CG (2015) The role of citrullinated protein antibodies in predicting erosive disease in rheumatoid arthritis: a systematic literature review and meta-analysis. Int J Rheumatol 2015:728610CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, Ronnelid J, Harris HE, Ulfgren AK, Rantapaa-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54:38–46CrossRefGoogle Scholar
  35. 35.
    De Rycke L, Peene I, Hoffman IE, Kruithof E, Union A, Meheus L, Lebeer K, Wyns B, Vincent C, Mielants H, Boullart L, Serre G, Veys EM, De Keyser F (2004) Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis 63:1587–1593CrossRefGoogle Scholar
  36. 36.
    Machold KP, Stamm TA, Nell VP, Pflugbeil S, Aletaha D, Steiner G, Uffmann M, Smolen JS (2007) Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease. Rheumatology 46:342–349Google Scholar
  37. 37.
    van der Woude D, Rantapaa-Dahlqvist S, Ioan-Facsinay A, Onnekink C, Schwarte CM, Verpoort KN, Drijfhout JW, Huizinga TW, Toes RE, Pruijn GJ (2010) Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann Rheum Dis 69:1554–1561Google Scholar
  38. 38.
    Brink M, Hansson M, Mathsson L, Jakobsson PJ, Holmdahl R, Hallmans G, Stenlund H, Ronnelid J, Klareskog L, Rantapaa-Dahlqvist S (2013) Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum 65:899–910CrossRefGoogle Scholar
  39. 39.
    Rombouts Y, Ewing E, van de Stadt LA, Selman MH, Trouw LA, Deelder AM, Huizinga TW, Wuhrer M, van Schaardenburg D, Toes RE, Scherer HU (2015) Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann Rheum Dis 74:234–241CrossRefGoogle Scholar
  40. 40.
    Scherer HU, van der Woude D, Willemze A, Trouw LA, Knevel R, Syversen SW, van der Linden MP, Lie B, Huizinga TW, van der Heijde DM, van der Helm-van Mil AH, Kvien TK, Toes RE (2011) Distinct ACPA fine specificities, formed under the influence of HLA shared epitope alleles, have no effect on radiographic joint damage in rheumatoid arthritis. Ann Rheum Dis 70:1461–1464CrossRefGoogle Scholar
  41. 41.
    van Beers JJ, Willemze A, Jansen JJ, Engbers GH, Salden M, Raats J, Drijfhout JW, van der Helm-van Mil AH, Toes RE, Pruijn GJ (2013) ACPA fine-specificity profiles in early rheumatoid arthritis patients do not correlate with clinical features at baseline or with disease progression. Arthritis Res Ther 15:R140CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kastbom A, Forslind K, Ernestam S, Geborek P, Karlsson JA, Petersson IF, Saevarsdottir S, Klareskog L, van Vollenhoven RF, Lundberg K (2016) Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial. Ann Rheum Dis 75:356–361CrossRefGoogle Scholar
  43. 43.
    Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GM, van Veelen PA, Levarht NE, van der Helm-van Mil AH, Cerami A, Huizinga TW, Toes RE, Trouw LA (2011) Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci USA 108:17372–17377Google Scholar
  44. 44.
    Fluckiger R, Harmon W, Meier W, Loo S, Gabbay KH (1981) Hemoglobin carbamylation in uremia. N Engl J Med 304:823–827CrossRefGoogle Scholar
  45. 45.
    Ospelt C, Bang H, Feist E, Camici GG, Keller S, Detert J, Kramer A, Gay S, Ghannam K, Burmester GR (2017) Carbamylation of vimentin is inducible by smoking and represents an independent autoantigen in rheumatoid arthritis. Ann Rheum Dis 76:1176–1183CrossRefGoogle Scholar
  46. 46.
    Dekkers JS, Verheul MK, Stoop JN, Liu B, Ioan-Facsinay A, van Veelen PA, de Ru AH, Janssen GMC, Hegen M, Rapecki S, Huizinga TWJ, Trouw LA, Toes REM (2017) Breach of autoreactive B cell tolerance by post-translationally modified proteins. Ann Rheum Dis. Google Scholar
  47. 47.
    Kumar S, Pangtey G, Gupta R, Rehan HS, Gupta LK (2017) Assessment of anti-CarP antibodies, disease activity and quality of life in rheumatoid arthritis patients on conventional and biological disease-modifying antirheumatic drugs. Reumatologia 55:4–9Google Scholar
  48. 48.
    Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, Jakobsson PJ, Baum W, Nimmerjahn F, Szarka E, Sarmay G, Krumbholz G, Neumann E, Toes R, Scherer HU, Catrina AI, Klareskog L, Jurdic P, Schett G (2012) Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 122:1791–1802CrossRefGoogle Scholar
  49. 49.
    Orsolini G, Caimmi C, Viapiana O, Idolazzi L, Fracassi E, Gatti D, Adami G, Rossini M (2017) Titer-dependent effect of anti-citrullinated protein antibodies on systemic bone mass in rheumatoid arthritis patients. Calcif Tissue Int 101:17–23CrossRefGoogle Scholar
  50. 50.
    Llorente I, Merino L, Ortiz AM, Escolano E, Gonzalez-Ortega S, Garcia-Vicuna R, Garcia-Vadillo JA, Castaneda S, Gonzalez-Alvaro I (2017) Anti-citrullinated protein antibodies are associated with decreased bone mineral density: baseline data from a register of early arthritis patients. Rheumatol Int 37:799–806CrossRefGoogle Scholar
  51. 51.
    Bugatti S, Bogliolo L, Vitolo B, Manzo A, Montecucco C, Caporali R (2016) Anti-citrullinated protein antibodies and high levels of rheumatoid factor are associated with systemic bone loss in patients with early untreated rheumatoid arthritis. Arthritis Res Ther 18:226CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Kleyer A, Finzel S, Rech J, Manger B, Krieter M, Faustini F, Araujo E, Hueber AJ, Harre U, Engelke K, Schett G (2014) Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis 73:854–860Google Scholar
  53. 53.
    Hecht C, Englbrecht M, Rech J, Schmidt S, Araujo E, Engelke K, Finzel S, Schett G (2015) Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann Rheum Dis 74:2151–2156CrossRefGoogle Scholar
  54. 54.
    Engdahl C, Bang H, Dietel K, Lang SC, Harre U, Schett G (2017) Periarticular bone loss in arthritis is induced by autoantibodies against citrullinated vimentin. J Bone Miner Res 32:1681–1691CrossRefGoogle Scholar
  55. 55.
    Krishnamurthy A, Joshua V, Haj Hensvold A, Jin T, Sun M, Vivar N, Ytterberg AJ, Engstrom M, Fernandes-Cerqueira C, Amara K, Magnusson M, Wigerblad G, Kato J, Jimenez-Andrade JM, Tyson K, Rapecki S, Lundberg K, Catrina SB, Jakobsson PJ, Svensson C, Malmstrom V, Klareskog L, Wahamaa H, Catrina AI (2016) Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis 75:721–729Google Scholar
  56. 56.
    Van Steendam K, Tilleman K, De Ceuleneer M, De Keyser F, Elewaut D, Deforce D (2010) Citrullinated vimentin as an important antigen in immune complexes from synovial fluid of rheumatoid arthritis patients with antibodies against citrullinated proteins. Arthritis Res Ther 12:R132CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Mathsson L, Lampa J, Mullazehi M, Ronnelid J (2006) Immune complexes from rheumatoid arthritis synovial fluid induce FcgammaRIIa dependent and rheumatoid factor correlated production of tumour necrosis factor-alpha by peripheral blood mononuclear cells. Arthritis Res Ther 8:R64CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Clavel C, Nogueira L, Laurent L, Iobagiu C, Vincent C, Sebbag M, Serre G (2008) Induction of macrophage secretion of tumor necrosis factor alpha through Fcgamma receptor IIa engagement by rheumatoid arthritis-specific autoantibodies to citrullinated proteins complexed with fibrinogen. Arthritis Rheum 58:678–688CrossRefGoogle Scholar
  59. 59.
    Schett G, Gravallese E (2012) Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol 8:656–664CrossRefGoogle Scholar
  60. 60.
    Braun T, Zwerina J (2011) Positive regulators of osteoclastogenesis and bone resorption in rheumatoid arthritis. Arthritis Res Ther 13:235CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Harre U, Schett G (2017) Cellular and molecular pathways of structural damage in rheumatoid arthritis. Semin Immunopathol 39:355–363CrossRefGoogle Scholar
  62. 62.
    Harre U, Keppeler H, Ipseiz N, Derer A, Poller K, Aigner M, Schett G, Herrmann M, Lauber K (2012) Moonlighting osteoclasts as undertakers of apoptotic cells. Autoimmunity 45:612–619CrossRefGoogle Scholar
  63. 63.
    Seeling M, Hillenhoff U, David JP, Schett G, Tuckermann J, Lux A, Nimmerjahn F (2013) Inflammatory monocytes and Fcgamma receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. Proc Natl Acad Sci USA 110:10729–10734CrossRefGoogle Scholar
  64. 64.
    Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8:34–47CrossRefGoogle Scholar
  65. 65.
    Takayanagi H (2010) New immune connections in osteoclast formation. Ann N Y Acad Sci 1192:117–123CrossRefGoogle Scholar
  66. 66.
    Harre U, Lang SC, Pfeifle R, Rombouts Y, Fruhbeisser S, Amara K, Bang H, Lux A, Koeleman CA, Baum W, Dietel K, Grohn F, Malmstrom V, Klareskog L, Kronke G, Kocijan R, Nimmerjahn F, Toes RE, Herrmann M, Scherer HU, Schett G (2015) Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 6:6651CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Arnold JN, Wormald MR, Sim RB, Rudd PM, Dwek RA (2007) The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol 25:21–50CrossRefGoogle Scholar
  68. 68.
    Bohm S, Schwab I, Lux A, Nimmerjahn F (2012) The role of sialic acid as a modulator of the anti-inflammatory activity of IgG. Semin Immunopathol 34:443–453CrossRefGoogle Scholar
  69. 69.
    Anthony RM, Wermeling F, Karlsson MC, Ravetch JV (2008) Identification of a receptor required for the anti-inflammatory activity of IVIG. Proc Natl Acad Sci USA 105:19571–19578Google Scholar
  70. 70.
    Massoud AH, Yona M, Xue D, Chouiali F, Alturaihi H, Ablona A, Mourad W, Piccirillo CA, Mazer BD (2014) Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J Allergy Clin Immunol 133:853–863CrossRefGoogle Scholar
  71. 71.
    Scallon BJ, Tam SH, McCarthy SG, Cai AN, Raju TS (2007) Higher levels of sialylated Fc glycans in immunoglobulin G molecules can adversely impact functionality. Mol Immunol 44:1524–1534CrossRefGoogle Scholar
  72. 72.
    Scherer HU, van der Woude D, Ioan-Facsinay A, el Bannoudi H, Trouw LA, Wang J, Haupl T, Burmester GR, Deelder AM, Huizinga TW, Wuhrer M, Toes RE (2010) Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum 62:1620–1629CrossRefGoogle Scholar
  73. 73.
    Kokkonen H, Mullazehi M, Berglin E, Hallmans G, Wadell G, Ronnelid J, Rantapaa-Dahlqvist S (2011) Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res Ther 13:R13CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Suwannalai P, van de Stadt LA, Radner H, Steiner G, El-Gabalawy HS, Jol-van der Zijde CM, van Tol MJ, van Schaardenburg D, Huizinga TWJ, Toes REM, Trouw LA (2012) Avidity maturation of anti-citrullinated protein antibodies in rheumatoid arthritis. Arthritis Rheum 64:1323–1328CrossRefGoogle Scholar
  75. 75.
    Pfeifle R, Rothe T, Ipseiz N, Scherer HU, Culemann S, Harre U, Ackermann JA, Seefried M, Kleyer A, Uderhardt S, Haugg B, Hueber AJ, Daum P, Heidkamp GF, Ge C, Bohm S, Lux A, Schuh W, Magorivska I, Nandakumar KS, Lonnblom E, Becker C, Dudziak D, Wuhrer M, Rombouts Y, Koeleman CA, Toes R, Winkler TH, Holmdahl R, Herrmann M, Bluml S, Nimmerjahn F, Schett G, Kronke G (2017) Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol 18:104–113Google Scholar
  76. 76.
    Anquetil F, Clavel C, Offer G, Serre G, Sebbag M (2015) IgM and IgA rheumatoid factors purified from rheumatoid arthritis sera boost the Fc receptor- and complement-dependent effector functions of the disease-specific anti-citrullinated protein autoantibodies. J Immunol 194:3664–3674CrossRefGoogle Scholar
  77. 77.
    Sokolove J, Johnson DS, Lahey LJ, Wagner CA, Cheng D, Thiele GM, Michaud K, Sayles H, Reimold AM, Caplan L, Cannon GW, Kerr G, Mikuls TR, Robinson WH (2014) Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis Rheum 66:813–821Google Scholar
  78. 78.
    Lacey DL, Boyle WJ, Simonet WS, Kostenuik PJ, Dougall WC, Sullivan JK, San Martin J, Dansey R (2012) Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 11:401–419CrossRefGoogle Scholar
  79. 79.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319CrossRefGoogle Scholar
  80. 80.
    Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T, Higashio K (1997) Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun 234:137–142CrossRefGoogle Scholar
  81. 81.
    Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, Tomoyasu A, Yano K, Goto M, Murakami A, Tsuda E, Morinaga T, Higashio K, Udagawa N, Takahashi N, Suda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597–3602CrossRefGoogle Scholar
  82. 82.
    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ, Simonet WS (1998) Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12:1260–1268CrossRefGoogle Scholar
  83. 83.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian YX, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle WJ (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176CrossRefGoogle Scholar
  84. 84.
    Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS 3rd, Frankel WN, Lee SY, Choi Y (1997) TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem 272:25190–25194Google Scholar
  85. 85.
    Joseph Lorenzo MH, Yongwon, Choi (2010) Hiroshi takayanagi. Osteoimmunology 1. Elsevier, AmsterdamGoogle Scholar
  86. 86.
    McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ (2006) Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354:821–831CrossRefGoogle Scholar
  87. 87.
    Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765CrossRefGoogle Scholar
  88. 88.
    Larussa T, Suraci E, Nazionale I, Leone I, Montalcini T, Abenavoli L, Imeneo M, Pujia A, Luzza F (2012) No evidence of circulating autoantibodies against osteoprotegerin in patients with celiac disease. World J Gastroenterol 18:1622–1627CrossRefGoogle Scholar
  89. 89.
    Hauser B, Riches PL, Gilchrist T, Visconti MR, Wilson JF, Ralston SH (2015) Autoantibodies to osteoprotegerin are associated with increased bone resorption in rheumatoid arthritis. Ann Rheum Dis 74:1631–1632CrossRefGoogle Scholar
  90. 90.
    Duskin A, Eisenberg RA (2010) The role of antibodies in inflammatory arthritis. Immunol Rev 233:112–125CrossRefGoogle Scholar
  91. 91.
    Bultink IEM (2017) Bone disease in connective tissue disease/systemic lupus erythematosus. Calcif Tissue Int. PubMedCentralGoogle Scholar
  92. 92.
    Mease PJ (2011) Psoriatic arthritis: update on pathophysiology, assessment and management. Ann Rheum Dis 70(Suppl 1):i77–i84CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUK
  2. 2.Department of Internal Medicine 3 – Rheumatology and ImmunologyFriedrich-Alexander-University Erlangen-Nürnberg (FAU), Universitätsklinikum ErlangenErlangenGermany

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