Skip to main content

Advertisement

SpringerLink
Log in

Bone as a Target Organ in Rheumatic Disease: Impact on Osteoclasts and Osteoblasts

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Dysregulated bone remodeling occurs when there is an imbalance between bone resorption and bone formation. In rheumatic diseases, including rheumatoid arthritis (RA) and seronegative spondyloarthritis, systemic and local factors disrupt the process of physiologic bone remodeling. Depending upon the local microenvironment, cell types, and local mechanical forces, inflammation results in very different effects on bone, promoting bone loss in the joints and in periarticular and systemic bone in RA and driving bone formation at enthesial and periosteal sites in diseases such as ankylosing spondylitis (AS), included within the classification of axial spondyloarthritis. There has been a great deal of interest in the role of osteoclasts in these processes and much has been learned over the past decade about osteoclast differentiation and function. It is now appreciated that osteoblast-mediated bone formation is also inhibited in the RA joint, limiting the repair of erosions. In contrast, osteoblasts function to produce new bone in AS. The Wnt and BMP signaling pathways have emerged as critical in the regulation of osteoblast function and the outcome for bone in rheumatic diseases, and these pathways have been implicated in both bone loss in RA and bone formation in AS. These pathways provide potential novel approaches for therapeutic intervention in diseases in which inflammation impacts bone.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Schett G, Gravallese E (2012) Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol 8:656–664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gravallese EM, Goldring SR (2000) Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis. Arthritis Rheum 43:2143–2151

    Article  CAS  PubMed  Google Scholar 

  3. Gravallese EM, Goldring SR, Schett G (2015) The role of the immune system in the local and systemic bone loss in inflammatory arthritis, in Osteimmunology: interaction of the Immune and skeletal systems, 2nd edn. Academic Press, London, Burlington MA, San Diego CA

    Google Scholar 

  4. Deodhar AA, Woolf AD (1996) Bone mass measurement and bone metabolism in rheumatoid arthritis: a review. Br J Rheumatol 35:309–322

    Article  CAS  PubMed  Google Scholar 

  5. Walsh NC, Gravallese EM (2004) Bone loss in inflammatory arthritis: mechanisms and treatment strategies. Curr Opin Rheumatol 16:419–427

    Article  PubMed  Google Scholar 

  6. Aho K, Heliovaara M, Maatela J, Tuomi T, Palosuo T (1991) Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 18:1282–1284

    CAS  PubMed  Google Scholar 

  7. Rantapaa-Dahlqvist S, de Jong BA, Berglin E et al (2003) Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 48:2741–2749

    Article  PubMed  CAS  Google Scholar 

  8. Arkema EV, Goldstein BL, Robinson W et al (2013) Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study. Arthritis Res Ther 15:R159

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. 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 2015:728610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kleyer A, Finzel S, Rech J et al (2014) Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis 73:854–860

    Article  PubMed  Google Scholar 

  11. Pettit AR, Ji H, von Stechow D et al (2001) TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. Am J Pathol 159:1689–1699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Redlich K, Hayer S, Ricci R et al (2002) Osteoclasts are essential for TNF-alpha-mediated joint destruction. J Clin Invest 110:1419–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 152:943–951

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kong YY, Feige U, Sarosi I et al (1999) Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304–309

    Article  CAS  PubMed  Google Scholar 

  15. Gravallese EM, Manning C, Tsay A et al (2000) Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum 43:250–258

    Article  CAS  PubMed  Google Scholar 

  16. 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:R76

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Walsh NC, Gravallese EM (2010) Bone remodeling in rheumatic disease: a question of balance. Immunol Rev 233:301–312

    Article  CAS  PubMed  Google Scholar 

  18. Schett G, Coates LC, Ash ZR, Finzel S, Conaghan PG (2011) Structural damage in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: traditional views, novel insights gained from TNF blockade, and concepts for the future. Arthritis Res Ther 13(Suppl 1):S4

    PubMed  PubMed Central  Google Scholar 

  19. Tsui FW, Tsui HW, Akram A, Haroon N, Inman RD (2014) The genetic basis of ankylosing spondylitis: new insights into disease pathogenesis. Appl Clin Genet 7:105–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. FitzGerald O, Haroon M, Giles JT, Winchester R (2015) Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype. Arthritis Res Ther 17:115

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Lories RJ, Luyten FP, de Vlam K (2009) Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis. Arthritis Res Ther 11:221

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Bromley M, Woolley DE (1984) Chondroclasts and osteoclasts at subchondral sites of erosion in the rheumatoid joint. Arthritis Rheum 27:968–975

    Article  CAS  PubMed  Google Scholar 

  23. Suzuki Y, Nishikaku F, Nakatuka M, Koga Y (1998) Osteoclast-like cells in murine collagen induced arthritis. J Rheumatol 25:1154–1160

    CAS  PubMed  Google Scholar 

  24. Romas E, Bakharevski O, Hards DK et al (2000) Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis Rheum 43:821–826

    Article  CAS  PubMed  Google Scholar 

  25. Kuratani T, Nagata K, Kukita T, Hotokebuchi T, Nakasima A, Iijima T (1998) Induction of abundant osteoclast-like multinucleated giant cells in adjuvant arthritic rats with accompanying disordered high bone turnover. Histol Histopathol 13:751–759

    CAS  PubMed  Google Scholar 

  26. Schett G, Redlich K, Hayer S et al (2003) Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice. Arthritis Rheum 48:2042–2051

    Article  CAS  PubMed  Google Scholar 

  27. Romas E, Sims NA, Hards DK et al (2002) Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Am J Pathol 161:1419–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Herrak P, Gortz B, Hayer S et al (2004) Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis. Arthritis Rheum 50:2327–2337

    Article  CAS  PubMed  Google Scholar 

  29. Sims NA, Green JR, Glatt M et al (2004) Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis. Arthritis Rheum 50:2338–2346

    Article  CAS  PubMed  Google Scholar 

  30. Jarrett SJ, Conaghan PG, Sloan VS et al (2006) Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum 54:1410–1414

    Article  CAS  PubMed  Google Scholar 

  31. Deodhar A, Dore RK, Mandel D et al (2010) Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients. Arthritis Care Res (Hoboken) 62:569–574

    Article  CAS  Google Scholar 

  32. Cohen SB, Dore RK, Lane NE 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 Rheum 58:1299–1309

    Article  CAS  PubMed  Google Scholar 

  33. Sugimoto T, Matsumoto T, Hosoi T et al (2015) Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT). Osteoporos Int 26:765–774

    Article  CAS  PubMed  Google Scholar 

  34. Wei S, Kitaura H, Zhou P, Ross FP, Teitelbaum SL (2005) IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115:282–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jovanovic DV, Di Battista JA, Martel-Pelletier J et al (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160:3513–3521

    CAS  PubMed  Google Scholar 

  36. Kotake S, Udagawa N, Takahashi N et al (1999) IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 103:1345–1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lubberts E, van den Bersselaar L, Oppers-Walgreen B et al (2003) IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol 170:2655–2662

    Article  CAS  PubMed  Google Scholar 

  38. Hashizume M, Hayakawa N, Mihara M (2008) IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology (Oxford) 47:1635–1640

    Article  CAS  Google Scholar 

  39. Yao Z, Li P, Zhang Q et al (2006) Tumor necrosis factor-alpha increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J Biol Chem 281:11846–11855

    Article  CAS  PubMed  Google Scholar 

  40. Jimi E, Nakamura I, Duong LT et al (1999) Interleukin 1 induces multinucleation and bone-resorbing activity of osteoclasts in the absence of osteoblasts/stromal cells. Exp Cell Res 247:84–93

    Article  CAS  PubMed  Google Scholar 

  41. Suzuki M, Hashizume M, Yoshida H, Shiina M, Mihara M (2011) Intercellular adhesion molecule-1 on synovial cells attenuated interleukin-6-induced inhibition of osteoclastogenesis induced by receptor activator for nuclear factor kappaB ligand. Clin Exp Immunol 163:88–95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yoshitake F, Itoh S, Narita H, Ishihara K, Ebisu S (2008) Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways. J Biol Chem 283:11535–11540

    Article  CAS  PubMed  Google Scholar 

  43. Axmann R, Bohm C, Kronke G, Zwerina J, Smolen J, Schett G (2009) Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo. Arthritis Rheum 60:2747–2756

    Article  CAS  PubMed  Google Scholar 

  44. Boe A, Baiocchi M, Carbonatto M, Papoian R, Serlupi-Crescenzi O (1999) Interleukin 6 knock-out mice are resistant to antigen-induced experimental arthritis. Cytokine 11:1057–1064

    Article  CAS  PubMed  Google Scholar 

  45. Kotake S, Sato K, Kim KJ et al (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 11:88–95

    Article  CAS  PubMed  Google Scholar 

  46. Takagi N, Mihara M, Moriya Y et al (1998) Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum 41:2117–2121

    Article  CAS  PubMed  Google Scholar 

  47. Jimenez-Boj E, Nobauer-Huhmann I, Hanslik-Schnabel B et al (2007) Bone erosions and bone marrow edema as defined by magnetic resonance imaging reflect true bone marrow inflammation in rheumatoid arthritis. Arthritis Rheum 56:1118–1124

    Article  PubMed  Google Scholar 

  48. Haavardsholm EA, Boyesen P, Ostergaard M, Schildvold A, Kvien TK (2008) Magnetic resonance imaging findings in 84 patients with early rheumatoid arthritis: bone marrow oedema predicts erosive progression. Ann Rheum Dis 67:794–800

    Article  CAS  PubMed  Google Scholar 

  49. Hetland ML, Ejbjerg B, Horslev-Petersen K et al (2009) MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA). Ann Rheum Dis 68:384–390

    Article  CAS  PubMed  Google Scholar 

  50. Dalbeth N, Smith T, Gray S et al (2009) Cellular characterisation of magnetic resonance imaging bone oedema in rheumatoid arthritis; implications for pathogenesis of erosive disease. Ann Rheum Dis 68:279–282

    Article  CAS  PubMed  Google Scholar 

  51. Smolen JS, Van Der Heijde DM, St Clair EW et al (2006) Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 54:702–710

    Article  CAS  PubMed  Google Scholar 

  52. Nishimoto N, Hashimoto J, Miyasaka N et al (2007) Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis 66:1162–1167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fleischmann R, Kremer J, Cush J et al (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367:495–507

    Article  CAS  PubMed  Google Scholar 

  54. van Vollenhoven RF, Fleischmann R, Cohen S et al (2012) Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 367:508–519

    Article  PubMed  CAS  Google Scholar 

  55. Lee EB, Fleischmann R, Hall S et al (2014) Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 370:2377–2386

    Article  PubMed  CAS  Google Scholar 

  56. Stewart A, Mackenzie LM, Black AJ, Reid DM (2004) Predicting erosive disease in rheumatoid arthritis. A longitudinal study of changes in bone density using digital X-ray radiogrammetry: a pilot study. Rheumatology (Oxford) 43:1561–1564

    Article  CAS  Google Scholar 

  57. Shimizu S, Shiozawa S, Shiozawa K, Imura S, Fujita T (1985) Quantitative histologic studies on the pathogenesis of periarticular osteoporosis in rheumatoid arthritis. Arthritis Rheum 28:25–31

    Article  CAS  PubMed  Google Scholar 

  58. Nishimura K, Sugiyama D, Kogata Y et al (2007) Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 146:797–808

    Article  PubMed  Google Scholar 

  59. Saeki Y, Kudo-Tanaka E, Ohshima S et al (2013) Baseline anti-citrullinated peptide antibody (ACPA) titers and serum interleukin-6 (IL-6) levels possibly predict progression of bone destruction in early stages of rheumatoid arthritis (ERA). Rheumatol Int 33:451–456

    Article  CAS  PubMed  Google Scholar 

  60. Hecht C., Englbrecht M., Rech J., et al. (2014) Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann Rheum Dis. doi:10.1136/annrheumdis-2014-205428

  61. Harre U, Kittan NA, Schett G (2014) Autoantibody-mediated bone loss. Curr Osteoporos Rep 12:17–21

    Article  PubMed  Google Scholar 

  62. 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:R64

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Clavel C, Nogueira L, Laurent L et al (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 58:678–688

    Article  CAS  PubMed  Google Scholar 

  64. 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 Rheum 62:1213–1223

    Article  CAS  PubMed  Google Scholar 

  65. Harre U, Georgess D, Bang H et al (2012) Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 122:1791–1802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Seeling M, Hillenhoff U, David JP et al (2013) Inflammatory monocytes and Fcgamma receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. Proc Natl Acad Sci U S A 110:10729–10734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Harre U, Lang SC, Pfeifle R et al (2015) Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 6:6651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kaneko Y, Nimmerjahn F, Ravetch JV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673

    Article  CAS  PubMed  Google Scholar 

  69. Berglin E, Padyukov L, Sundin U et al (2004) A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther 6:R303–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Nielen MM, van Schaardenburg D, Reesink HW et al (2004) Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 50:380–386

    Article  PubMed  Google Scholar 

  71. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  CAS  PubMed  Google Scholar 

  72. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114

    Article  CAS  PubMed  Google Scholar 

  73. Chen X, Liang H, Zhang J, Zen K, Zhang CY (2012) Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell 3:28–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chen X, Liang H, Zhang J, Zen K, Zhang CY (2012) Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol 22:125–132

    Article  CAS  PubMed  Google Scholar 

  75. Bobrie A, Colombo M, Raposo G, Thery C (2011) Exosome secretion: molecular mechanisms and roles in immune responses. Traffic 12:1659–1668

    Article  CAS  PubMed  Google Scholar 

  76. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C et al (2011) Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2:282

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Roccaro AM, Sacco A, Maiso P et al (2013) BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest 123:1542–1555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Duroux-Richard I, Jorgensen C, Apparailly F (2011) miRNAs and rheumatoid arthritis - promising novel biomarkers. Swiss Med Wkly 141:w13175

    PubMed  Google Scholar 

  79. Nakasa T, Shibuya H, Nagata Y, Niimoto T, Ochi M (2011) The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum 63:1582–1590

    Article  CAS  PubMed  Google Scholar 

  80. Ceribelli A, Nahid MA, Satoh M, Chan EK (2011) MicroRNAs in rheumatoid arthritis. FEBS Lett 585:3667–3674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Zhu S, Pan W, Song X et al (2012) The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-alpha. Nat Med 18:1077–1086

    Article  CAS  PubMed  Google Scholar 

  82. Kurowska-Stolarska M, Alivernini S, Ballantine LE et al (2011) MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci U S A 108:11193–11198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tili E, Michaille JJ, Cimino A et al (2007) Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol 179:5082–5089

    Article  CAS  PubMed  Google Scholar 

  84. Bluml S, Bonelli M, Niederreiter B et al (2011) Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice. Arthritis Rheum 63:1281–1288

    Article  PubMed  CAS  Google Scholar 

  85. Sugatani T, Vacher J, Hruska KA (2011) A microRNA expression signature of osteoclastogenesis. Blood 117:3648–3657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang J, Zhao H, Chen J et al (2012) Interferon-beta-induced miR-155 inhibits osteoclast differentiation by targeting SOCS1 and MITF. FEBS Lett 586:3255–3262

    Article  CAS  PubMed  Google Scholar 

  87. de la Rica L, Garcia-Gomez A, Comet NR et al (2015) NF-kappaB-direct activation of microRNAs with repressive effects on monocyte-specific genes is critical for osteoclast differentiation. Genome Biol 16:2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Nakamachi Y., Ohnuma K., Uto K., Noguchi Y., Saegusa J., Kawano S. (2015) MicroRNA-124 inhibits the progression of adjuvant-induced arthritis in rats. Ann Rheum Dis. doi:10.1136/annrheumdis-2014-206417

  89. Crane JL, Cao X (2014) Bone marrow mesenchymal stem cells and TGF-beta signaling in bone remodeling. J Clin Invest 124:466–472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ (2012) Update on Wnt signaling in bone cell biology and bone disease. Gene 492:1–18

    Article  CAS  PubMed  Google Scholar 

  91. Sanchez-Duffhues G., Hiepen C., Knaus P., Ten Dijke P. (2015) Bone morphogenetic protein signaling in bone homeostasis. Bone. doi:10.1016/j.bone.2015.05.025

  92. Regard J. B., Zhong Z., Williams B. O., Yang Y. (2012) Wnt signaling in bone development and disease: making stronger bone with Wnts. Cold Spring Harb Perspect Biol 4:12

  93. Morvan F, Boulukos K, Clement-Lacroix P et al (2006) Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J Bone Miner Res 21:934–945

    Article  CAS  PubMed  Google Scholar 

  94. Li J, Sarosi I, Cattley RC et al (2006) Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39:754–766

    Article  CAS  PubMed  Google Scholar 

  95. Bodine PV, Zhao W, Kharode YP et al (2004) The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice. Mol Endocrinol 18:1222–1237

    Article  CAS  PubMed  Google Scholar 

  96. Yao W, Cheng Z, Shahnazari M, Dai W, Johnson ML, Lane NE (2010) Overexpression of secreted frizzled-related protein 1 inhibits bone formation and attenuates parathyroid hormone bone anabolic effects. J Bone Miner Res 25:190–199

    Article  CAS  PubMed  Google Scholar 

  97. Diarra D, Stolina M, Polzer K et al (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat Med 13:156–163

    Article  CAS  PubMed  Google Scholar 

  98. Daoussis D, Andonopoulos AP (2011) The emerging role of Dickkopf-1 in bone biology: is it the main switch controlling bone and joint remodeling? Semin Arthritis Rheum 41:170–177

    Article  CAS  PubMed  Google Scholar 

  99. Matzelle MM, Gallant MA, Condon KW et al (2012) Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum 64:1540–1550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Li X, Zhang Y, Kang H et al (2005) Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem 280:19883–19887

    Article  CAS  PubMed  Google Scholar 

  101. Staehling-Hampton K, Proll S, Paeper BW et al (2002) A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 110:144–152

    Article  PubMed  Google Scholar 

  102. Balemans W, Patel N, Ebeling M et al (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91–97

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. van Lierop AH, Hamdy NA, van Egmond ME, Bakker E, Dikkers FG, Papapoulos SE (2013) Van Buchem disease: clinical, biochemical, and densitometric features of patients and disease carriers. J Bone Miner Res 28:848–854

    Article  PubMed  CAS  Google Scholar 

  104. Balemans W, Ebeling M, Patel N et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537–543

    Article  CAS  PubMed  Google Scholar 

  105. Hamersma H, Gardner J, Beighton P (2003) The natural history of sclerosteosis. Clin Genet 63:192–197

    Article  CAS  PubMed  Google Scholar 

  106. Li X, Ominsky MS, Niu QT et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23:860–869

    Article  PubMed  Google Scholar 

  107. Winkler DG, Sutherland MK, Geoghegan JC et al (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chen G, Deng C, Li YP (2012) TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci 8:272–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gaur T, Hussain S, Mudhasani R et al (2010) Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse. Dev Biol 340:10–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wei J, Shi Y, Zheng L et al (2012) miR-34s inhibit osteoblast proliferation and differentiation in the mouse by targeting SATB2. J Cell Biol 197:509–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lian JB, Stein GS, van Wijnen AJ et al (2012) MicroRNA control of bone formation and homeostasis. Nat Rev Endocrinol 8:212–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hassan MQ, Gordon JA, Beloti MM et al (2010) A network connecting Runx2, SATB2, and the miR-23a ∼ 27a ∼ 24-2 cluster regulates the osteoblast differentiation program. Proc Natl Acad Sci U S A 107:19879–19884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Moller DU, Boonen A, Hetland ML et al (2009) Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure. Ann Rheum Dis 68:1585–1590

    Article  PubMed  CAS  Google Scholar 

  114. Dohn UM, Ejbjerg B, Boonen A et al (2011) No overall progression and occasional repair of erosions despite persistent inflammation in adalimumab-treated rheumatoid arthritis patients: results from a longitudinal comparative MRI, ultrasonography, CT and radiography study. Ann Rheum Dis 70:252–258

    Article  PubMed  Google Scholar 

  115. Finzel S, Rech J, Schmidt S et al (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 70:1587–1593

    Article  CAS  PubMed  Google Scholar 

  116. Finzel S, Rech J, Schmidt S, Engelke K, Englbrecht M, Schett G (2013) Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: a micro CT study. Ann Rheum Dis 72:396–400

    Article  CAS  PubMed  Google Scholar 

  117. Gilbert L, He X, Farmer P et al (2000) Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology 141:3956–3964

    CAS  PubMed  Google Scholar 

  118. Gilbert L, He X, Farmer P et al (2002) Expression of the osteoblast differentiation factor RUNX2 (Cbfa1/AML3/Pebp2alpha A) is inhibited by tumor necrosis factor-alpha. J Biol Chem 277:2695–2701

    Article  CAS  PubMed  Google Scholar 

  119. Kaneki H, Guo R, Chen D et al (2006) Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 281:4326–4333

    Article  CAS  PubMed  Google Scholar 

  120. Jilka RL, Weinstein RS, Bellido T, Parfitt AM, Manolagas SC (1998) Osteoblast programmed cell death (apoptosis): modulation by growth factors and cytokines. J Bone Miner Res 13:793–802

    Article  CAS  PubMed  Google Scholar 

  121. 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 2:559–565

    Article  CAS  PubMed  Google Scholar 

  122. Hengartner NE, Fiedler J, Ignatius A, Brenner RE (2013) IL-1beta inhibits human osteoblast migration. Mol Med 19:36–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Liu XH, Kirschenbaum A, Yao S, Levine AC (2005) Cross-talk between the interleukin-6 and prostaglandin E(2) signaling systems results in enhancement of osteoclastogenesis through effects on the osteoprotegerin/receptor activator of nuclear factor-{kappa}B (RANK) ligand/RANK system. Endocrinology 146:1991–1998

    Article  CAS  PubMed  Google Scholar 

  124. Walsh NC, Reinwald S, Manning CA et al (2009) Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J Bone Miner Res 24:1572–1585

    Article  CAS  PubMed  Google Scholar 

  125. de Rooy DP, Yeremenko NG, Wilson AG et al (2013) Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann Rheum Dis 72:769–775

    Article  PubMed  CAS  Google Scholar 

  126. Yu B, Chang J, Liu Y et al (2014) Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-kappaB. Nat Med 20:1009–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lories RJ, Derese I, Luyten FP (2005) Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest 115:1571–1579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lories RJ, Schett G (2012) Pathophysiology of new bone formation and ankylosis in spondyloarthritis. Rheum Dis Clin North Am 38:555–567

    Article  PubMed  Google Scholar 

  129. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS (2014) Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A 111:12097–12102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Bollow M, Fischer T, Reisshauer H et al (2000) Quantitative analyses of sacroiliac biopsies in spondyloarthropathies: T cells and macrophages predominate in early and active sacroiliitis- cellularity correlates with the degree of enhancement detected by magnetic resonance imaging. Ann Rheum Dis 59:135–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Appel H, Ruiz-Heiland G, Listing J et al (2009) Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 60:3257–3262

    Article  PubMed  Google Scholar 

  132. Tsui F. W., Tsui H. W., Las Heras F., Pritzker K. P., Inman R. D. (2013) Serum levels of novel noggin and sclerostin-immune complexes are elevated in ankylosing spondylitis. Ann Rheum Dis 73:1873–1879

  133. Chen XX, Baum W, Dwyer D et al (2013) Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis. Ann Rheum Dis 72:1732–1736

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Uderhardt S, Diarra D, Katzenbeisser J et al (2010) Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis 69:592–597

    Article  CAS  PubMed  Google Scholar 

  135. Haynes KR, Pettit AR, Duan R et al (2012) Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res Ther 14:R253

    Article  PubMed  PubMed Central  Google Scholar 

  136. Heiland GR, Appel H, Poddubnyy D et al (2012) High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 71:572–574

    Article  CAS  PubMed  Google Scholar 

  137. Klingberg E, Nurkkala M, Carlsten H, Forsblad-d'Elia H (2014) Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis. J Rheumatol 41:1349–1356

    Article  PubMed  Google Scholar 

  138. Chen HA, Chen CH, Lin YJ et al (2010) Association of bone morphogenetic proteins with spinal fusion in ankylosing spondylitis. J Rheumatol 37:2126–2132

    Article  CAS  PubMed  Google Scholar 

  139. Park MC, Park YB, Lee SK (2008) Relationship of bone morphogenetic proteins to disease activity and radiographic damage in patients with ankylosing spondylitis. Scand J Rheumatol 37:200–204

    Article  CAS  PubMed  Google Scholar 

  140. 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 74:304–305

    Article  CAS  PubMed  Google Scholar 

  141. Colbert RA, Tran TM, Layh-Schmitt G (2014) HLA-B27 misfolding and ankylosing spondylitis. Mol Immunol 57:44–51

    Article  CAS  PubMed  Google Scholar 

  142. Sherlock JP, Joyce-Shaikh B, Turner SP et al (2012) IL-23 induces spondyloarthropathy by acting on ROR-gammat + CD3 + CD4-CD8- entheseal resident T cells. Nat Med 18:1069–1076

    Article  CAS  PubMed  Google Scholar 

  143. Benjamin M, McGonagle D (2001) The anatomical basis for disease localisation in seronegative spondyloarthropathy at entheses and related sites. J Anat 199:503–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Sherlock JP, Buckley CD, Cua DJ (2014) The critical role of interleukin-23 in spondyloarthropathy. Mol Immunol 57:38–43

    Article  CAS  PubMed  Google Scholar 

  145. Van Praet L, Van den Bosch FE, Jacques P et al (2013) Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model. Ann Rheum Dis 72:414–417

    Article  PubMed  Google Scholar 

  146. Ciccia F, Accardo-Palumbo A, Rizzo A et al (2014) Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. Ann Rheum Dis 73:1566–1574

    Article  CAS  PubMed  Google Scholar 

  147. Smith JA, Colbert RA (2014) Review: The interleukin-23/interleukin-17 axis in spondyloarthritis pathogenesis: Th17 and beyond. Arthritis Rheumatol 66:231–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lee YH, Choi SJ, Ji JD, Song GG (2012) Associations between interleukin-23R polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis. Inflamm Res 61:143–149

    Article  CAS  PubMed  Google Scholar 

  149. Kang YK, Zhang MC (2014) IL-23 promotes osteoclastogenesis in osteoblast-osteoclast co-culture system. Genet Mol Res 13:4673–4679

    Article  CAS  PubMed  Google Scholar 

  150. Chen L, Wei XQ, Evans B, Jiang W, Aeschlimann D (2008) IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. Eur J Immunol 38:2845–2854

    Article  CAS  PubMed  Google Scholar 

  151. Yago T, Nanke Y, Kawamoto M et al (2007) IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats. Arthritis Res Ther 9:R96

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. McGonagle D, Stockwin L, Isaacs J, Emery P (2001) An enthesitis based model for the pathogenesis of spondyloarthropathy. additive effects of microbial adjuvant and biomechanical factors at disease sites. J Rheumatol 28:2155–2159

    CAS  PubMed  Google Scholar 

  153. Jacques P, Lambrecht S, Verheugen E et al (2014) Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis 73:437–445

    Article  PubMed  Google Scholar 

  154. van der Heijde D, Landewe R, Einstein S et al (2008) Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum 58:1324–1331

    Article  PubMed  CAS  Google Scholar 

  155. van der Heijde D, Landewe R, Baraliakos X et al (2008) Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 58:3063–3070

    Article  PubMed  Google Scholar 

  156. van der Heijde D, Salonen D, Weissman BN et al (2009) Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther 11:R127

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Haroon N, Inman RD, Learch TJ et al (2013) The impact of tumor necrosis factor alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum 65:2645–2654

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Baraliakos X, Haibel H, Listing J, Sieper J, Braun J (2014) Continuous long-term anti-TNF therapy does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis 73:710–715

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of Interest

Rebecca Baum and Ellen Gravallese declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Medicine and Division of Rheumatology, University of Massachusetts Medical School, Lazare Research Building Suite 223, 364 Plantation Street, Worcester, MA, 01605, USA

    Rebecca Baum & Ellen M. Gravallese

Authors
  1. Rebecca Baum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ellen M. Gravallese
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ellen M. Gravallese.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baum, R., Gravallese, E.M. Bone as a Target Organ in Rheumatic Disease: Impact on Osteoclasts and Osteoblasts. Clinic Rev Allerg Immunol 51, 1–15 (2016). https://doi.org/10.1007/s12016-015-8515-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-015-8515-6

Keywords

Search

Navigation