Osteologie 2021; 30(04): 319-325
DOI: 10.1055/a-1577-2719
Review

New Insights into Bone Loss in RA

Neue Erkenntnisse zum Knochenverlust bei RA
Darja Andreev
1   Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
2   Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
,
Aline Bozec
1   Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
2   Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
› Institutsangaben

Abstract

The negative impact of rheumatoid arthritis (RA) on bone mineral density is well characterized. Notably, articular bone erosion is a central feature of RA, leading to joint damage and disabilities. In addition, the axial and appendicular skeleton can be affected, which secondly manifests in bone fracture. The main trigger of RA-associated bone loss is excessive bone degradation by osteoclasts and impaired bone formation by osteoblasts. In particular, the inflammatory status, reflected by high level of proinflammatory cytokines, receptor activator of nuclear factor κB ligand (RANKL), and autoantibodies induces the formation of bone-resorbing osteoclasts. Today, antirheumatic therapy effectively hampers synovial inflammation and bone erosion. However, current medication is unable to repair established bone lesions. This review outlines the knowledge gained about the pathophysiology of rheumatoid arthritis and the molecular mechanisms that promote osteoclast-mediated bone erosion and inhibit osteoblast-related bone formation, pointing out possible new intervention for inflammatory bone disease.

Zusammenfassung

Negative Auswirkungen der rheumatoiden Arthritis (RA) auf die Knochendichte werden in vielen Patienten beobachtet. Insbesondere Knochenerosionen im Gelenk sind ein zentrales Merkmal von RA, was in der Regel zu Gelenksschädigung und Bewegungseinschränkungen führt. Darüber hinaus können auch das axiale und appendikuläre Skelett betroffen sein, was im weiteren Verlauf Knochenbrüche verursachen kann. Die Hauptursache für RA-assoziierten Knochenverlust ist ein übermäßiger Knochenabbau durch Osteoklasten und ein beeinträchtigter Knochenaufbau durch Osteoblasten. Entzündliche Faktoren wie proinflammatorische Zytokine, receptor activator of nuclear factor κB ligand (RANKL) und Autoantikörper begünstigen v. a. die Bildung von knochenresorbierenden Osteoklasten. Die heutzutage verordnete antirheumatische Medikation hemmt effektiv die Gelenksentzündung und den Knochenabbau. Allerdings sind die derzeitigen Medikamente nicht in der Lage, bereits entstandene Knochenläsionen zu reparieren. Dieser Übersichtsartikel beschreibt die bisher gewonnenen Erkenntnisse über die Pathophysiologie der rheumatoiden Arthritis und die molekularen Mechanismen, die einerseits die Osteoklasten-vermittelte Knochenerosion induzieren und andererseits zu einer Hemmung der Knochenneubildung durch Osteoblasten führen. Es werden mögliche neue Therapieansätze betrachtet, die insbesondere die knochenschädigende Auswirkung von RA aufheben sollen.



Publikationsverlauf

Eingereicht: 23. Juni 2021

Angenommen: 02. August 2021

Artikel online veröffentlicht:
17. September 2021

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  • References

  • 1 Safiri S, Kolahi AA, Hoy D, Smith E, Bettampadi D, Mansournia MA. et al. Global, regional and national burden of rheumatoid arthritis 1990–2017: a systematic analysis of the Global Burden of Disease study 2017. Ann Rheum Dis 2019; 78: 1463-1471
  • 2 Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS. et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018; 4: 18001
  • 3 McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. The New England journal of medicine 2011; 365: 2205-2219
  • 4 Wegierska M, Dura M, Blumfield E, Zuchowski P, Waszczak M, Jeka S. Osteoporosis diagnostics in patients with rheumatoid arthritis. Reumatologia 2016; 54: 29-34
  • 5 Smolen JS, Landewe RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020; 79: 685-699
  • 6 Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K. Genetics of rheumatoid arthritis: 2018 status. Ann Rheum Dis 2019; 78: 446-453
  • 7 Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016; 388: 2023-2038
  • 8 de Brito Rocha S, Baldo DC, Andrade LEC. Clinical and pathophysiologic relevance of autoantibodies in rheumatoid arthritis. Adv Rheumatol 2019; 59: 2
  • 9 Nygaard G, Firestein GS. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nature reviews Rheumatology 2020; 16: 316-333
  • 10 Culemann S, Gruneboom A, Nicolas-Avila JA, Weidner D, Lammle KF, Rothe T. et al. Locally renewing resident synovial macrophages provide a protective barrier for the joint. Nature 2019; 572: 670–675
  • 11 Sokolove J, Zhao X, Chandra PE, Robinson WH. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcgamma receptor. Arthritis and rheumatism 2011; 63: 53-62
  • 12 Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nature medicine 2014; 20: 62-68
  • 13 Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nature reviews Rheumatology 2014; 10: 593-601
  • 14 Kleyer A, Schett G. Arthritis and bone loss: a hen and egg story. Curr Opin Rheumatol 2014; 26: 80-84
  • 15 Jacome-Galarza CE, Percin GI, Muller JT, Mass E, Lazarov T, Eitler J. et al. Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 2019; 568: 541–545
  • 16 Hasegawa T, Kikuta J, Sudo T, Matsuura Y, Matsui T, Simmons S. et al. Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. Nature immunology 2019; 20: 1631-1643
  • 17 McDonald MM, Khoo WH, Ng PY, Xiao Y, Zamerli J, Thatcher P. et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 2021; 184: 1940
  • 18 Feng X, Teitelbaum SL. Osteoclasts: New Insights. Bone Res 2013; 1: 11-26
  • 19 Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nature reviews Immunology 2007; 7: 292-304
  • 20 Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-319
  • 21 Pettit AR, Ji H, von Stechow D, Muller R, Goldring SR, Choi Y. et al. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis. The American journal of pathology 2001; 159: 1689-1699
  • 22 Kamijo S, Nakajima A, Ikeda K, Aoki K, Ohya K, Akiba H. et al. Amelioration of bone loss in collagen-induced arthritis by neutralizing anti-RANKL monoclonal antibody. Biochemical and biophysical research communications 2006; 347: 124-132
  • 23 Meednu N, Zhang H, Owen T, Sun W, Wang V, Cistrone C. et al. Production of RANKL by Memory B Cells: A Link Between B Cells and Bone Erosion in Rheumatoid Arthritis. Arthritis & rheumatology 2016; 68: 805-816
  • 24 Danks L, Komatsu N, Guerrini MM, Sawa S, Armaka M, Kollias G. et al. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis 2016; 75: 1187-1195
  • 25 Liao C, Zhang C, Yang Y. Pivotal Roles of Interleukin-17 as the Epicenter of Bone Loss Diseases. Curr Pharm Des 2017; 23: 6302-6309
  • 26 Panagopoulos PK, Lambrou GI. Bone erosions in rheumatoid arthritis: recent developments in pathogenesis and therapeutic implications. J Musculoskelet Neuronal Interact 2018; 18: 304-319
  • 27 Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nature reviews Rheumatology. 2012; 8: 656-664
  • 28 Kleyer A, Finzel S, Rech J, Manger B, Krieter M, Faustini F. et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis 2014; 73: 854-860
  • 29 Harre U, Georgess D, Bang H, Bozec A, Axmann R, Ossipova E. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. The Journal of clinical investigation 2012; 122: 1791-1802
  • 30 Krishnamurthy A, Joshua V, Haj Hensvold A, Jin T, Sun M, Vivar N. et al. Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann Rheum Dis 2016; 75: 721-729
  • 31 Harre U, Lang SC, Pfeifle R, Rombouts Y, Fruhbeisser S, Amara K. et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nature communications 2015; 6: 6651
  • 32 Pfeifle R, Rothe T, Ipseiz N, Scherer HU, Culemann S, Harre U. et al. Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nature immunology 2017; 18: 104-113
  • 33 Amarasekara DS, Kim S, Rho J. Regulation of Osteoblast Differentiation by Cytokine Networks. International journal of molecular sciences. 2021; 22: 2851
  • 34 Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D. et al. Dickkopf-1 is a master regulator of joint remodeling. Nature medicine 2007; 13: 156-163
  • 35 Heiland GR, Zwerina K, Baum W, Kireva T, Distler JH, Grisanti M. et al. Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. Ann Rheum Dis 2010; 69: 2152-2159
  • 36 Chen XX, Baum W, Dwyer D, Stock M, Schwabe K, Ke HZ. et al. Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis. Ann Rheum Dis 2013; 72: 1732-1736
  • 37 Adam S, Simon N, Steffen U, Andes FT, Scholtysek C, Muller DIH. et al. JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function. Sci Transl Med 2020; 12: eaay4447. doi: 10.1126/scitranslmed.aay4447
  • 38 Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW. et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015; 523: 221–225
  • 39 Bozec A, Zaiss MM, Kagwiria R, Voll R, Rauh M, Chen Z. et al. T cell costimulation molecules CD80/86 inhibit osteoclast differentiation by inducing the IDO/tryptophan pathway. Sci Transl Med 2014; 6: 235ra60
  • 40 Bozec A, Zaiss MM. T Regulatory Cells in Bone Remodelling. Curr Osteoporos Rep 2017; 15: 121-125
  • 41 Chen Z, Andreev D, Oeser K, Krljanac B, Hueber A, Kleyer A. et al. Th2 and eosinophil responses suppress inflammatory arthritis. Nature communications 2016; 7: 11596
  • 42 Rauber S, Luber M, Weber S, Maul L, Soare A, Wohlfahrt T. et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nature medicine 2017; 23: 938-944
  • 43 Omata Y, Frech M, Primbs T, Lucas S, Andreev D, Scholtysek C. et al. Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice. Cell reports 2018; 24: 169-180
  • 44 Andreev D, Liu M, Kachler K, Llerins Perez M, Kirchner P, Kolle J. et al. Regulatory eosinophils induce the resolution of experimental arthritis and appear in remission state of human rheumatoid arthritis. Ann Rheum Dis 2020. doi: 10.1136/annrheumdis-2020-218902