Calcified Tissue International

, Volume 102, Issue 5, pp 533–546 | Cite as

Bone Loss in Rheumatoid Arthritis: Basic Mechanisms and Clinical Implications

  • Jae-hyuck Shim
  • Zheni Stavre
  • Ellen M. Gravallese
Review

Abstract

Patients with rheumatoid arthritis (RA) have historically developed progressive damage of articular bone and cartilage, which correlates with disability over time. In addition, these patients are prone to periarticular and systemic bone loss, carrying additional morbidity. In contrast to what is seen in many other rheumatic diseases, the impact of inflammation on bone in RA is uniquely destructive. Loss of articular bone (erosions) and periarticular bone (demineralization) is a result of excessive bone resorption and markedly limited bone formation. There has been tremendous progress in preventing net bone loss in RA with the advent of disease-modifying agents, including biologic agents and small molecules, that both limit inflammation and may have a direct impact on the prevention of cytokine- and antibody-driven osteoclastogenesis. However, repair of existing bone erosions, although feasible, is observed infrequently. Lack of repair is a consequence of suppression of osteoblast function and bone formation by some of the same mechanisms that promote osteoclastogenesis and bone resorption. As new agents are introduced to control inflammation in RA, and novel mechanisms to target synovitis are identified, it may be possible in the future to fully repair damaged bone.

Keywords

Osteoclasts Osteoblasts Rheumatoid arthritis Synovitis Erosions 

Notes

Conflict of interest

EG reports research Grants from AbbVie Inc. and Eli Lilly and Company, as well as personal fees from GlaxoSmithKline PLC, Novartis Pharmaceuticals Corporation, Sanofi Genzyme, and Eli Lilly and Company. She receives royalties from UpToDate. Jae-hyuck Shim and Zheni Stavre declare that they have no conflicts of interest.

References

  1. 1.
    Gough AK, Lilley J, Eyre S, Holder RL, Emery P (1994) Generalised bone loss in patients with early rheumatoid arthritis. Lancet 344:23–27PubMedGoogle Scholar
  2. 2.
    Schett G, Gravallese E (2012) Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol 8:656–664PubMedPubMedCentralGoogle Scholar
  3. 3.
    Scott DL, Pugner K, Kaarela K, Doyle DV, Woolf A, Holmes J, Hieke K (2000) The links between joint damage and disability in rheumatoid arthritis. Rheumatology 39:122–132PubMedGoogle Scholar
  4. 4.
    McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219PubMedGoogle Scholar
  5. 5.
    Gravallese EM, Goldring SR, Schett G (2014) The role of the immune system in the local and systemic bone loss of inflammatory arthritis. In: Lorenzo J, Horowitz M, Choi Y, Takayanagi H, Schett G (eds) Osteoimmunology, 2nd edn. Elsevier, AmsterdamGoogle Scholar
  6. 6.
    Sokolove J, Bromberg R, Deane KD, Lahey LJ, Derber LA, Chandra PE, Edison JD, Gilliland WR, Tibshirani RJ, Norris JM et al (2012) Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7:e35296PubMedPubMedCentralGoogle Scholar
  7. 7.
    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 Rheumatol Dis 69:1554–1561Google Scholar
  8. 8.
    Vossenaar ER, Zendman AJ, van Venrooij WJ, Pruijn GJ (2003) PAD, a growing family of citrullinating enzymes: genes, features and involvement in disease. Bioessays 25:1106–1118PubMedGoogle Scholar
  9. 9.
    Bos WH, Wolbink GJ, Boers M, Tijhuis GJ, de Vries N, van der Horst-Bruinsma IE, Tak PP, van de Stadt RJ, van der Laken CJ, Dijkmans BA et al (2010) Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann Rheumatol Dis 69:490–494Google Scholar
  10. 10.
    van Steenbergen HW, Mangnus L, Reijnierse M, Huizinga TW, van der Helm-van AHM (2016) Clinical factors, anticitrullinated peptide antibodies and MRI-detected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis. Ann Rheumatol Dis 75:1824–1830Google Scholar
  11. 11.
    Toes RE, Huizinga TJ (2015) Update on autoantibodies to modified proteins. Curr Opin Rheumatol 27:262–267PubMedGoogle Scholar
  12. 12.
    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:R132PubMedPubMedCentralGoogle Scholar
  13. 13.
    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:R64PubMedPubMedCentralGoogle Scholar
  14. 14.
    Amara K, Steen J, Murray F, Morbach H, Fernandez-Rodriguez BM, Joshua V, Engstrom M, Snir O, Israelsson L, Catrina AI et al (2013) Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J Exp Med 210:445–455PubMedPubMedCentralGoogle Scholar
  15. 15.
    Lu MC, Lai NS, Yu HC, Huang HB, Hsieh SC, Yu CL (2010) Anti-citrullinated protein antibodies bind surface-expressed citrullinated Grp78 on monocyte/macrophages and stimulate tumor necrosis factor alpha production. Arthritis Rheumatol 62:1213–1223Google Scholar
  16. 16.
    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 Rheumatol 58:678–688Google Scholar
  17. 17.
    van Steenbergen HW, Ajeganova S, Forslind K, Svensson B, vander Helm-van AHM (2015) The effects of rheumatoid factor and anticitrullinated peptide antibodies on bone erosions in rheumatoid arthritis. Ann Rheum Dis 74:e3PubMedGoogle Scholar
  18. 18.
    Mustila A, Korpela M, Haapala AM, Kautiainen H, Laasonen L, Mottonen T, Leirisalo-Repo M, Ilonen J, Jarvenpaa S, Luukkainen R et al (2011) Anti-citrullinated peptide antibodies and the progression of radiographic joint erosions in patients with early rheumatoid arthritis treated with FIN-RACo combination and single disease-modifying antirheumatic drug strategies. Clin Exp Rheumatol 29:500–505PubMedGoogle Scholar
  19. 19.
    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 74:2151–2156PubMedGoogle Scholar
  20. 20.
    van Schaardenburg D, Nielen MM, Lems WF, Twisk JW, Reesink HW, van de Stadt RJ, van der Horst-Bruinsma IE, de Koning MH, Habibuw MR, Dijkmans BA (2011) Bone metabolism is altered in preclinical rheumatoid arthritis. Ann Rheum Dis 70:1173–1174PubMedGoogle Scholar
  21. 21.
    Kleyer A, Finzel S, Rech J, Manger B, Krieter M, Faustini F, Araujo E, Hueber AJ, Harre U, Engelke K et al (2014) Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis 73:854–860PubMedGoogle Scholar
  22. 22.
    Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E, Jakobsson PJ, Baum W, Nimmerjahn F, Szarka E et al (2012) Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 122:1791–1802PubMedPubMedCentralGoogle Scholar
  23. 23.
    Krishnamurthy A, Joshua V, Haj Hensvold A, Jin T, Sun M, Vivar N, Ytterberg AJ, Engstrom M, Fernandes-Cerqueira C, Amara K et al (2016) Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis 75:721–729PubMedGoogle Scholar
  24. 24.
    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 110:10729–10734PubMedPubMedCentralGoogle Scholar
  25. 25.
    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 25:21–50PubMedGoogle Scholar
  26. 26.
    Harre U, Lang SC, Pfeifle R, Rombouts Y, Fruhbeisser S, Amara K, Bang H, Lux A, Koeleman CA, Baum W et al (2015) Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 6:6651PubMedPubMedCentralGoogle Scholar
  27. 27.
    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 34:443–453PubMedGoogle Scholar
  28. 28.
    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:R13PubMedPubMedCentralGoogle Scholar
  29. 29.
    Rombouts Y, Ewing E, van de Stadt LA, Selman MH, Trouw LA, Deelder AM, Huizinga TW, Wuhrer M, van Schaardenburg D, Toes RE et al (2015) Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann Rheum Dis 74:234–241PubMedGoogle Scholar
  30. 30.
    Shi J, Knevel R, Suwannalai P, van der Linden MP, Janssen GM, van Veelen PA, Levarht NE,, Cerami AH, Huizinga A, van der Helm-van AHM et al (2011) Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci USA 108:17372–17377PubMedPubMedCentralGoogle Scholar
  31. 31.
    Brink M, Verheul MK, Ronnelid J, Berglin E, Holmdahl R, Toes RE, Klareskog L, Trouw LA, Rantapaa-Dahlqvist S (2015) Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage. Arthritis Res Ther 17:25PubMedPubMedCentralGoogle Scholar
  32. 32.
    Koppejan H, Trouw LA, Sokolove J, Lahey LJ, Huizinga TJ, Smolik IA, Robinson DB, El-Gabalawy HS, Toes RE, Hitchon CA (2016) Role of anti-carbamylated protein antibodies compared to anti-citrullinated protein antibodies in indigenous North Americans with rheumatoid arthritis, their first-degree relatives, and healthy controls. Arthritis Rheumatol 68:2090–2098PubMedGoogle Scholar
  33. 33.
    Ajeganova S, van Steenbergen HW, Verheul MK, Forslind K, Hafstrom I, Toes RE, Huizinga TW, Svensson B, Trouw LA, van der Helm-van AHM (2017) The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor. Ann Rheum Dis 76:112–118PubMedGoogle Scholar
  34. 34.
    Sharp JT, Lidsky MD, Collins LC, Moreland J (1971) Methods of scoring the progression of radiologic changes in rheumatoid arthritis. Correlation of radiologic, clinical and laboratory abnormalities. Arthritis Rheumatol 14:706–720Google Scholar
  35. 35.
    Kay J, Gravallese EM (2013) Rheumatoid arthritis: erosion defined: back to basics. Nat Rev Rheumatol 9:323–324PubMedPubMedCentralGoogle Scholar
  36. 36.
    Gladman DD (2006) Clinical, radiological, and functional assessment in psoriatic arthritis: is it different from other inflammatory joint diseases? Ann Rheum Dis 65(Suppl 3):iii22–iii24PubMedPubMedCentralGoogle Scholar
  37. 37.
    Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69:1580–1588PubMedGoogle Scholar
  38. 38.
    van der Heijde D, van der Helm-van Mil AH, Aletaha D, Bingham CO, Burmester GR, Dougados M, Emery P, Felson D, Knevel R, Kvien TK et al (2013) EULAR definition of erosive disease in light of the 2010 ACR/EULAR rheumatoid arthritis classification criteria. Ann Rheum Dis 72:479–481PubMedGoogle Scholar
  39. 39.
    Baum R, Gravallese EM (2014) Impact of inflammation on the osteoblast in rheumatic diseases. Curr Osteoporos Rep 12:9–16PubMedPubMedCentralGoogle Scholar
  40. 40.
    Teitelbaum SL, Ross FP (2003) Genetic regulation of osteoclast development and function. Nat Rev Genet 4:638–649PubMedGoogle Scholar
  41. 41.
    Schroeder TM, Jensen ED, Westendorf JJ (2005) Runx2: a master organizer of gene transcription in developing and maturing osteoblasts. Birth Defects Res C Embryo Today 75:213–225PubMedGoogle Scholar
  42. 42.
    Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29PubMedGoogle Scholar
  43. 43.
    Sanchez-Duffhues G, Hiepen C, Knaus P, Dijke TP (2015) Bone morphogenetic protein signaling in bone homeostasis. Bone 80:43–59PubMedGoogle Scholar
  44. 44.
    Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ (2012) Update on Wnt signaling in bone cell biology and bone disease. Gene 492:1–18PubMedGoogle Scholar
  45. 45.
    Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, Mantila SM, Gluhak-Heinrich J, Bellido TM, Harris SE et al (2008) Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem 283:5866–5875PubMedGoogle Scholar
  46. 46.
    Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, Elliott R, Colombero A, Elliott G, Scully S et al (1998) Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176PubMedGoogle Scholar
  47. 47.
    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T et al (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319PubMedGoogle Scholar
  48. 48.
    Pettit AR, Ji H, von Stechow D, Müller R, Goldring SR, Choi Y, Benoist C, Gravallese EM (2001) TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 159:1689–1699PubMedPubMedCentralGoogle Scholar
  49. 49.
    Redlich K, Hayer S, Ricci R, David JP, Tohidast-Akrad M, Kollias G, Steiner G, Smolen JS, Wagner EF, Schett G (2002) Osteoclasts are essential for TNF-alpha-mediated joint destruction. J Clin Invest 110:1419–1427PubMedPubMedCentralGoogle Scholar
  50. 50.
    Brennan FM, McInnes IB (2008) Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537–3545PubMedPubMedCentralGoogle Scholar
  51. 51.
    van Tuyl LH, Voskuyl AE, Boers M, Geusens P, Landewe RB, Dijkmans BA, Lems WF (2010) Baseline RANKL:OPG ratio and markers of bone and cartilage degradation predict annual radiological progression over 11 years in rheumatoid arthritis. Ann Rheum Dis 69:1623–1628PubMedGoogle Scholar
  52. 52.
    Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR (1998) Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol 152:943–951PubMedPubMedCentralGoogle Scholar
  53. 53.
    Haynes D, Crotti T, Weedon H, Slavotinek J, Au V, Coleman M, Roberts-Thomson PJ, Ahern M, Smith MD (2008) Modulation of RANKL and osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis in response to disease-modifying antirheumatic drug treatment and correlation with radiologic outcome. Arthritis Rheumatol 59:911–920Google Scholar
  54. 54.
    Matzelle MM, Gallant MA, Condon KW, Walsh NC, Manning CA, Stein GS, Lian JB, Burr DB, Gravallese EM (2012) Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheumatol 64:1540–1550Google Scholar
  55. 55.
    Walsh NC, Reinwald S, Manning CA, Condon KW, Iwata K, Burr DB, Gravallese EM (2009) Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res 24:1572–1585PubMedGoogle Scholar
  56. 56.
    Yeremenko N, Zwerina K, Rigter G, Pots D, Fonseca JE, Zwerina J, Schett G, Baeten D (2015) Tumor necrosis factor and interleukin-6 differentially regulate Dkk-1 in the inflamed arthritic joint. Arthritis Rheumatol 67:2071–2075PubMedGoogle Scholar
  57. 57.
    Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, Korb A, Smolen J, Hoffmann M, Scheinecker C et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163PubMedGoogle Scholar
  58. 58.
    Wang SY, Liu YY, Ye H, Guo JP, Li R, Liu X, Li ZG (2011) Circulating Dickkopf-1 is correlated with bone erosion and inflammation in rheumatoid arthritis. J Rheumatol 38:821–827PubMedGoogle Scholar
  59. 59.
    Brunkow ME, Gardner JC, Van Ness J, Paeper BW, Kovacevich BR, Proll S, Skonier JE, Zhao L, Sabo PJ, Fu Y et al (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68:577–589PubMedPubMedCentralGoogle Scholar
  60. 60.
    Li X, Ominsky MS, Niu QT, Sun N, Daugherty B, D’Agostin D, Kurahara C, Gao Y, Cao J, Gong J et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869PubMedGoogle Scholar
  61. 61.
    Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887PubMedGoogle Scholar
  62. 62.
    Florio M, Gunasekaran K, Stolina M, Li X, Liu L, Tipton B, Salimi-Moosavi H, Asuncion FJ, Li C, Sun B et al (2016) A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. Nat Commun 7:11505PubMedPubMedCentralGoogle Scholar
  63. 63.
    Gravallese EM, Walsh NC (2011) Rheumatoid arthritis: repair of erosion in RA-shifting the balance to formation. Nat Rev Rheumatol 7:626–628PubMedPubMedCentralGoogle Scholar
  64. 64.
    Crotti TN, Smith MD, Weedon H, Ahern MJ, Findlay DM, Kraan M, Tak PP, Haynes DR (2002) Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann Rheum Dis 61:1047–1054PubMedPubMedCentralGoogle Scholar
  65. 65.
    Yarilina A, Xu K, Chen J, Ivashkiv LB (2011) TNF activates calcium-nuclear factor of activated T cells (NFAT)c1 signaling pathways in human macrophages. Proc Natl Acad Sci USA 108:1573–1578PubMedPubMedCentralGoogle Scholar
  66. 66.
    Kim N, Takami M, Rho J, Josien R, Choi Y (2002) A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med 195:201–209PubMedPubMedCentralGoogle Scholar
  67. 67.
    Herman S, Muller RB, Kronke G, Zwerina J, Redlich K, Hueber AJ, Gelse H, Neumann E, Muller-Ladner U, Schett G (2008) Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheumatol 58:3041–3050Google Scholar
  68. 68.
    Gilbert L, He X, Farmer P, Boden S, Kozlowski M, Rubin J, Nanes MS (2000) Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 141:3956–3964PubMedGoogle Scholar
  69. 69.
    Gilbert L, He X, Farmer P, Rubin J, Drissi H, van Wijnen AJ, Lian JB, Stein GS, Nanes MS (2002) Expression of the osteoblast differentiation factor RUNX2 (Cbfa1/AML3/Pebp2alpha A) is inhibited by tumor necrosis factor-alpha. J Biol Chem 277:2695–2701PubMedGoogle Scholar
  70. 70.
    Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115:282–290PubMedPubMedCentralGoogle Scholar
  71. 71.
    Stashenko P, Dewhirst FE, Rooney ML, Desjardins LA, Heeley JD (1987) Interleukin-1 beta is a potent inhibitor of bone formation in vitro. J Bone Miner Res 2:559–565PubMedGoogle Scholar
  72. 72.
    Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiki S, Matsuda T, Hirano T et al (1990) IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303PubMedGoogle Scholar
  73. 73.
    Takagi N, Mihara M, Moriya Y, Nishimoto N, Yoshizaki K, Kishimoto T, Takeda Y, Ohsugi Y (1998) Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheumatol 41:2117–2121Google Scholar
  74. 74.
    Smolen JS, Avila JC, Aletaha D (2012) Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction. Ann Rheum Dis 71:687–693PubMedGoogle Scholar
  75. 75.
    Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M et al (1999) Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 354:1932–1939PubMedGoogle Scholar
  76. 76.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedGoogle Scholar
  77. 77.
    Zhang F, Tanaka H, Kawato T, Kitami S, Nakai K, Motohashi M, Suzuki N, Wang CL, Ochiai K, Isokawa K et al. (2011). Interleukin-17A induces cathepsin K and MMP-9 expression in osteoclasts via celecoxib-blocked prostaglandin E2 in osteoblasts. Biochimie 93:296–305PubMedGoogle Scholar
  78. 78.
    Bush KA, Farmer KM, Walker JS, Kirkham BW (2002) Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheumatol 46:802–805Google Scholar
  79. 79.
    Lubberts E, Koenders MI, Oppers-Walgreen B, van den Bersselaar L, Coenen-de Roo CJ, Joosten LA, van den Berg WB (2004) Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. Arthritis Rheumatol 50:650–659Google Scholar
  80. 80.
    Adamopoulos IE, Suzuki E, Chao CC, Gorman D, Adda S, Maverakis E, Zarbalis K, Geissler R, Asio A, Blumenschein WM et al (2015) IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis. Ann Rheum Dis 74:1284–1292PubMedGoogle Scholar
  81. 81.
    Noack M, Miossec P (2014) Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13:668–677PubMedGoogle Scholar
  82. 82.
    Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V, Aelion JA, Lee SH, Codding CE, Kellner H et al (2013) Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 72:863–869PubMedGoogle Scholar
  83. 83.
    Hwang SJ, Choi B, Kang SS, Chang JH, Kim YG, Chung YH, Sohn DH, So MW, Lee CK, Robinson WH et al (2012) Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis. Arthritis Res Ther 14:R14PubMedPubMedCentralGoogle Scholar
  84. 84.
    Chemel M, Le Goff B, Brion R, Cozic C, Berreur M, Amiaud J, Bougras G, Touchais S, Blanchard F, Heymann MF et al (2012) Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients. Ann Rheum Dis 71:150–154PubMedGoogle Scholar
  85. 85.
    Zhang F, Ding R, Li P, Ma C, Song D, Wang X, Ma T, Bi L (2015) Interleukin-34 in rheumatoid arthritis: potential role in clinical therapy. Int J Clin Exp Med 8:7809–7815PubMedPubMedCentralGoogle Scholar
  86. 86.
    Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, Friday S, Li S, Patel RM, Subramanian V et al (2013) NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 5:178ra140Google Scholar
  87. 87.
    Cascao R, Rosario HS, Souto-Carneiro MM, Fonseca JE (2010) Neutrophils in rheumatoid arthritis: more than simple final effectors. Autoimmun Rev 9:531–535PubMedGoogle Scholar
  88. 88.
    Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241PubMedPubMedCentralGoogle Scholar
  89. 89.
    Remijsen Q, Berghe V, Wirawan T, Asselbergh E, Parthoens B, De Rycke E, Noppen R, Delforge S, Willems MJ, Vandenabeele P (2011) Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res 21:290–304PubMedGoogle Scholar
  90. 90.
    Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A (2010) Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 191:677–691PubMedPubMedCentralGoogle Scholar
  91. 91.
    Leshner M, Wang S, Lewis C, Zheng H, Chen XA, Santy L, Wang Y (2012) PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front Immunol 3:307PubMedPubMedCentralGoogle Scholar
  92. 92.
    Goh FG, Midwood KS (2012) Intrinsic danger: activation of Toll-like receptors in rheumatoid arthritis. Rheumatology 51:7–23PubMedGoogle Scholar
  93. 93.
    Tamaki Y, Takakubo Y, Hirayama T, Konttinen YT, Goodman SB, Yamakawa M, Takagi M (2011) Expression of Toll-like receptors and their signaling pathways in rheumatoid synovitis. J Rheumatol 38:810–820PubMedGoogle Scholar
  94. 94.
    Elshabrawy HA, Essani AE, Szekanecz Z, Fox DA, Shahrara S (2017) TLRs, future potential therapeutic targets for RA. Autoimmun Rev 16:103–113PubMedGoogle Scholar
  95. 95.
    Chamberlain ND, Vila OM, Volin MV, Volkov S, Pope RM, Swedler W, Mandelin AM 2nd, Shahrara S (2012). TLR5, a novel and unidentified inflammatory mediator in rheumatoid arthritis that correlates with disease activity score and joint TNF-alpha levels. J Immunol 189, 475–483PubMedPubMedCentralGoogle Scholar
  96. 96.
    Marriott I (2013) Apoptosis-associated uncoupling of bone formation and resorption in osteomyelitis. Front Cell Infect Microbiol 3:101PubMedPubMedCentralGoogle Scholar
  97. 97.
    Mihaly SR, Morioka S, Ninomiya-Tsuji J, Takaesu G (2014). Activated macrophage survival is coordinated by TAK1 binding proteins. PLoS ONE 9:e94982PubMedPubMedCentralGoogle Scholar
  98. 98.
    Takami M, Kim N, Rho J, Choi Y (2002) Stimulation by toll-like receptors inhibits osteoclast differentiation. J Immunol 169:1516–1523PubMedGoogle Scholar
  99. 99.
    Nam JL, Ramiro S, Gaujoux-Viala C, Takase K, Leon-Garcia M, Emery P, Gossec L, Landewe R, Smolen JS, Buch MH (2014) Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 73:516–528PubMedGoogle Scholar
  100. 100.
    Hazlewood GS, Barnabe C, Tomlinson G, Marshall D, Devoe D, Bombardier C (2016) Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis. BMJ 353:i1777PubMedPubMedCentralGoogle Scholar
  101. 101.
    Moreland LW, O’Dell JR, Paulus HE, Curtis JR, Bathon JM, Clair St, Bridges EW, Zhang SL Jr, McVie J, Howard TG et al (2012) A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheumatol 64:2824–2835Google Scholar
  102. 102.
    Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, Kincaid W, Porter D (2004) Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 364:263–269PubMedGoogle Scholar
  103. 103.
    Prevoo ML, van Gestel AM, van Thof MH, van Rijswijk MH, van de Putte LB, van Riel PL (1996) Remission in a prospective study of patients with rheumatoid arthritis. American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol 35:1101–1105PubMedGoogle Scholar
  104. 104.
    Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Mola M, Pavelka E, Sany K, Settas JL et al (2004) Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 363:675–681PubMedGoogle Scholar
  105. 105.
    Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheumatol 50:1400–1411Google Scholar
  106. 106.
    Emery P, Fleischmann R, van der Heijde D, Keystone EC, Genovese MC, Conaghan PG, Hsia EC, Xu W, Baratelle A, Beutler A et al (2011) The effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy. Arthritis Rheumatol 63:1200–1210Google Scholar
  107. 107.
    Keystone E, Heijde D, Mason D Jr, Landewe R, Vollenhoven RV, Combe B, Emery P, Strand V, Mease P, Desai C et al (2008) Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol 58:3319–3329Google Scholar
  108. 108.
    Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, Preiss R, Arulmani U, Widmer A, Gitton X et al (2011) Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord 12:153PubMedPubMedCentralGoogle Scholar
  109. 109.
    Ilowite NT, Prather K, Lokhnygina Y, Schanberg LE, Elder M, Milojevic D, Verbsky JW, Spalding SJ, Kimura Y, Imundo LF et al (2014) Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol 66:2570–2579PubMedPubMedCentralGoogle Scholar
  110. 110.
    Mertens M, Singh JA (2009) Anakinra for rheumatoid arthritis. Cochrane Database Syst Rev.  https://doi.org/10.1002/14651858.CD005121.pub3 PubMedGoogle Scholar
  111. 111.
    Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R, Investigators O (2008) Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371:987–997PubMedGoogle Scholar
  112. 112.
    Cooper S (2016) Sarilumab for the treatment of rheumatoid arthritis. Immunotherapy 8:249–250PubMedGoogle Scholar
  113. 113.
    Jiang Y, Genant HK, Watt I, Cobby M, Bresnihan B, Aitchison R, McCabe D (2000) A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheumatol 43:1001–1009Google Scholar
  114. 114.
    Bresnihan B (2001) The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 30:17–20PubMedGoogle Scholar
  115. 115.
    Turkstra E, Ng SK, Scuffham PA (2011) A mixed treatment comparison of the short-term efficacy of biologic disease modifying anti-rheumatic drugs in established rheumatoid arthritis. Curr Med Res Opin 27:1885–1897PubMedGoogle Scholar
  116. 116.
    Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, Ghogomu ET, Tugwell P (2009). A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 181:787–796PubMedPubMedCentralGoogle Scholar
  117. 117.
    Hoy SM (2015). Canakinumab: a review of its use in the management of systemic juvenile idiopathic arthritis. BioDrugs 29:133–142PubMedGoogle Scholar
  118. 118.
    Kubo S, Nakano K, Nakayamada S, Hirata S, Fukuyo S, Sawamukai N, Saito K, Tanaka Y (2016) Clinical, radiographic and functional efficacy of abatacept in routine care for rheumatoid arthritis patients: Abatacept Leading Trial for RA on Imaging Remission (ALTAIR) study. Clin Exp Rheumatol 34:834–841PubMedGoogle Scholar
  119. 119.
    Edwards JC, Cambridge G (2001) Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 40:205–211PubMedGoogle Scholar
  120. 120.
    Melet J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G (2013) Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheumatol 65:2783–2790Google Scholar
  121. 121.
    van de Veerdonk FL, Lauwerys B, Marijnissen RJ, Timmermans K, Di Padova F, Koenders MI, Gutierrez-Roelens I, Durez P, Netea MG, van der Meer JW et al (2011) The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheumatol 63:1507–1516Google Scholar
  122. 122.
    Akiyama M, Kaneko Y, Kondo H, Takeuchi T (2016) Comparison of the clinical effectiveness of tumour necrosis factor inhibitors and abatacept after insufficient response to tocilizumab in patients with rheumatoid arthritis. Clin Rheumatol 35:2829–2834PubMedGoogle Scholar
  123. 123.
    Porter D, van Melckebeke J, Dale J, Messow CM, McConnachie A, Walker A, Munro R, McLaren J, McRorie E, Packham J et al (2016) Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial. Lancet 388:239–247PubMedGoogle Scholar
  124. 124.
    Burmester GR, McInnes IB, Kremer J, Miranda P, Korkosz M, Vencovsky J, Rubbert-Roth A, Mysler E, Sleeman MA, Godwood A et al (2017) A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis 76:1020–1030PubMedGoogle Scholar
  125. 125.
    Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(Pt 2):297–314PubMedPubMedCentralGoogle Scholar
  126. 126.
    Villarino AV, Kanno Y, Ferdinand JR, O’Shea JJ (2015) Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 194:21–27PubMedPubMedCentralGoogle Scholar
  127. 127.
    Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, Warner JD, Tanaka M, Steward-Tharp SM, Gadina M et al (2011) Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol 186:4234–4243PubMedPubMedCentralGoogle Scholar
  128. 128.
    Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, Shurmur R, Singhal AK, Wei N, Rosengren S et al (2015) The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis 74:1311–1316PubMedGoogle Scholar
  129. 129.
    Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, Koncz T, Krishnaswami S, Wallenstein GV, Zang C et al (2014) Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 370:2377–2386PubMedGoogle Scholar
  130. 130.
    Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus-Gort RK, Luchi ME, Rooney TP et al (2015) Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis 74:333–340PubMedGoogle Scholar
  131. 131.
    Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, Wang L, Othman AA, Khan N, Pangan AL et al (2016) Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol 68:2857–2866PubMedPubMedCentralGoogle Scholar
  132. 132.
    Westhovens R, Taylor PC, Alten R, Pavlova D, Enriquez-Sosa F, Mazur M, Greenwald M, Van der Aa A, Vanhoutte F, Tasset C et al (2017) Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann Rheum Dis 76:998–1008PubMedGoogle Scholar
  133. 133.
    Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH, Psoriasis Study G et al (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2:52ra72PubMedGoogle Scholar
  134. 134.
    Blanco FJ, Moricke R, Dokoupilova E, Codding C, Neal J, Andersson M, Rohrer S, Richards H (2017) Secukinumab in active rheumatoid arthritis: a phase III randomized, double-blind, active comparator- and placebo-controlled study. Arthritis Rheumatol 69:1144–1153PubMedGoogle Scholar
  135. 135.
    Uluçkan Ö, Jimenez M, Karbach S, Jeschke A, Graña O, Keller J, Busse B, Croxford AL, Finzel S, Koenders M et al (2016) Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med 8:330ra337Google Scholar
  136. 136.
    Shaw AT, Maeda Y, Gravallese EM (2016) IL-17A deficiency promotes periosteal bone formation in a model of inflammatory arthritis. Arthritis Res Ther 18:104PubMedPubMedCentralGoogle Scholar
  137. 137.
    Osta B, Lavocat F, Eljaafari A, Miossec P (2014) Effects of interleukin-17A on osteogenic differentiation of isolated human mesenchymal stem cells. Front Immunol 5:425PubMedPubMedCentralGoogle Scholar
  138. 138.
    Lubberts E (2015) The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol 11:415–429PubMedGoogle Scholar
  139. 139.
    Fischer JA, Hueber AJ, Wilson S, Galm M, Baum W, Kitson C, Auer J, Lorenz SH, Moelleken J, Bader M et al (2015) Combined inhibition of tumor necrosis factor α and interleukin-17 as a therapeutic opportunity in rheumatoid arthritis: development and characterization of a novel bispecific antibody. Arthritis Rheumatol 67:51–62PubMedGoogle Scholar
  140. 140.
    Koenders MI, Marijnissen RJ, Devesa I, Lubberts E, Joosten LA, Roth J, van Lent PL, van de Loo FA, van den Berg WB (2011) Tumor necrosis factor-interleukin-17 interplay induces S100A8, interleukin-1beta, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: rationale for combination treatment during arthritis. Arthritis Rheumatol 63:2329–2339Google Scholar
  141. 141.
    Mease PJGM, Weinblatt M, Peloso PM, Chen K, Li Y, Mansikka HT, Khatri A, Othman AA, Wishart N, Liu J, Padley RJ (2016) Safety and efficacy of ABT-122, a TNF and IL-17–targeted dual variable domain (DVD)–Ig™, in psoriatic arthritis patients with inadequate response to methotrexate: results from a phase 2 trial. Arthritis Rheumatol 68:958Google Scholar
  142. 142.
    Ideguchi H, Ohno S, Hattori H, Senuma A, Ishigatsubo Y (2006) Bone erosions in rheumatoid arthritis can be repaired through reduction in disease activity with conventional disease-modifying antirheumatic drugs. Arthritis Res Ther 8:R76PubMedPubMedCentralGoogle Scholar
  143. 143.
    Finzel S, Rech J, Schmidt S, Engelke K, Englbrecht M, Stach C, Schett G (2011) Repair of bone erosions in rheumatoid arthritis treated with tumour necrosis factor inhibitors is based on bone apposition at the base of the erosion. Ann Rheum Dis 70:1587–1593PubMedGoogle Scholar
  144. 144.
    Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, Hensor E, Wakefield RJ, O’Connor PJ, Emery P (2008) An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheumatol 58:2958–2967Google Scholar
  145. 145.
    Poole KE, van Bezooijen RL, Loveridge N, Hamersma H, Papapoulos SE, Lowik CW, Reeve J (2005) Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J 19:1842–1844PubMedGoogle Scholar
  146. 146.
    Wehmeyer C, Frank S, Beckmann D, Bottcher M, Cromme C, Konig U, Fennen M, Held A, Paruzel P, Hartmann C et al (2016) Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction. Sci Transl Med 8:330ra335Google Scholar
  147. 147.
    Redlich K, Gortz B, Hayer S, Zwerina J, Doerr N, Kostenuik P, Bergmeister H, Kollias G, Steiner G, Smolen JS et al (2004) Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis. Am J Pathol 164:543–555PubMedPubMedCentralGoogle Scholar
  148. 148.
    Solomon DH, Kay J, Duryea J, Lu B, Bolster MB, Yood RA, Han R, Ball S, Coleman C, Lo E et al (2017) Effects of teriparatide on joint erosions in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol.  https://doi.org/10.1002/art.40156 Google Scholar
  149. 149.
    Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R et al (2008) Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheumatol 58:1299–1309Google Scholar
  150. 150.
    Takeuchi T, Tanaka Y, Ishiguro N, Yamanaka H, Yoneda T, Ohira T, Okubo N, Genant HK, van der Heijde, D (2016) Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial. Ann Rheum Dis 75:983–990PubMedGoogle Scholar
  151. 151.
    Mukherjee K, Chattopadhyay N (2016) Pharmacological inhibition of cathepsin K: a promising novel approach for postmenopausal osteoporosis therapy. Biochem Pharmacol 117:10–19PubMedGoogle Scholar
  152. 152.
    Lin TH, Yang RS, Tu HJ, Liou HC, Lin YM, Chuang WJ, Fu WM (2017) Inhibition of osteoporosis by the alphavbeta3 integrin antagonist of rhodostomin variants. Eur J Pharmacol 804:94–101PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Division of Rheumatology, Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA

Personalised recommendations