Effects of Autoantibodies on Osteoclasts

Abstract

The balance between bone forming osteoblasts and bone resorbing osteoclasts can be disturbed in autoimmune diseases resulting in local and systemic bone loss. It was long time believed that autoantibodies only indirectly contribute to bone loss by fueling the overall inflammation. However, in the last decade, more and more evidence emerged that autoantibodies and immune complexes directly activate osteoclasts and pre-osteoclasts by binding to Fcγ receptors (FcγRs) on the (pre)-osteoclast cell surface. This pro-osteoclastogenic effect seems to be dependent on the absence of sialic acid in the IgG Fc glycan, which is a typical feature of many autoantibodies. Clinical studies revealed the importance of autoantibody-mediated bone loss mainly in rheumatoid arthritis, but also in other diseases, such as celiac disease. In summary, the gained knowledge about autoantibody-mediated bone loss helps to better understand bone pathologies of autoimmune diseases. However, studies are still relatively limited and more research is needed to fully understand the impact of autoantibodies on bone and to develop future therapeutic strategies.

Zusammenfassung

Das Gleichgewicht zwischen knochenbildenden Osteoblasten und knochenresorbierenden Osteoklasten kann bei Autoimmunerkrankungen gestört sein, wodurch es zu lokalem und systemischem Knochenverlust kommt. Es wurde lange Zeit angenommen, dass Autoantikörper nur indirekt zum Knochenverlust beitragen, indem sie die Entzündung befeuern. In den letzten zehn Jahren gab es jedoch immer mehr Hinweise darauf, dass Autoantikörper und Immunkomplexe Osteoklasten und Präosteoklasten direkt aktivieren, indem sie an Fcγ-Rezeptoren (FcγRs) auf der (Prä-) Osteoklastenoberfläche binden. Diese pro-osteoklastogene Wirkung scheint von der Abwesenheit von Sialinsäure im IgG-Fc-Glykan abhängig zu sein, was ein typisches Merkmal vieler Autoantikörper ist. Klinische Studien zeigten die Bedeutung des autoantikörpervermittelten Knochenverlusts hauptsächlich bei rheumatoider Arthritis, aber auch bei anderen Krankheiten wie Zöliakie. Zusammengenommen hilft das gewonnene Wissen über autoantikörpervermittelten Knochenverlust, die Knochenpathologien von Autoimmunerkrankungen besser zu verstehen. Bisher gibt es jedoch nur relativ wenige Studien und es sind weitere Forschungsarbeiten erforderlich, um die Auswirkungen von Autoantikörpern auf den Knochen vollständig zu verstehen und zukünftige Therapiestrategien zu entwickeln.

Key words

bone loss - osteoclast - autoantibodies - autoimmunity - glycosylation

Schlüsselwörter

Knochenverlust - Osteoklast - Autoantikörper - Autoimmunität - Glykosylierung

• References

• 1 Wegner N, Lundberg K, Kinloch A. et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol Rev 2010; 233: 34-54
• 2 Harre U, Georgess D, Bang H. et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest 2012; 122: 1791-1802
• 3 Iseme RA, McEvoy M, Kelly B. et al. Is osteoporosis an autoimmune mediated disorder?. Bone Rep 2017; 7: 121-131
• 4 Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 2008; 8: 34-47
• 5 Harre U, Keppeler H, Ipseiz N. et al. Moonlighting osteoclasts as undertakers of apoptotic cells. Autoimmunity 2012; 45: 612-619
• 6 Harre U, Lang SC, Pfeifle R. et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 2015; 6: 6651
• 7 Seeling M, Hillenhoff U, David JP. et al. 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 2013; 110: 10729-10734
• 8 Negishi-Koga T, Gober HJ, Sumiya E. et al. Immune complexes regulate bone metabolism through FcRgamma signalling. Nat Commun 2015; 6: 6637
• 9 Humphrey MB, Nakamura MC. A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts. Clin Rev Allergy Immunol 2016; 51: 48-58
• 10 Takayanagi H. RANKL as the master regulator of osteoclast differentiation. J Bone Miner Metab 2021; 39: 13-18
• 11 Grotsch B, Lux A, Rombouts Y. et al. Fra1 Controls Rheumatoid Factor Autoantibody Production by Bone Marrow Plasma Cells and the Development of Autoimmune Bone Loss. J Bone Miner Res 2019; 34: 1352-1365
• 12 Koga T, Inui M, Inoue K. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 2004; 428: 758-763
• 13 Christensen AD, Haase C, Cook AD. et al. K/BxN Serum-Transfer Arthritis as a Model for Human Inflammatory Arthritis. Front Immunol 2016; 7: 213
• 14 Wang TT, Ravetch JV. Functional diversification of IgGs through Fc glycosylation. J Clin Invest 2019; 129: 3492-3498
• 15 Zauner G, Selman MH, Bondt A. et al. Glycoproteomic analysis of antibodies. Mol Cell Proteomics 2013; 12: 856-865
• 16 Sehic E, Westerlund A, Lagerquist MK. et al. Immunoglobulin G complexes without sialic acids enhance osteoclastogenesis but do not affect arthritis-mediated bone loss. Scand J Immunol 2021; 93: e13009
• 17 Westhrin M, Kovcic V, Zhang Z. et al. Monoclonal immunoglobulins promote bone loss in multiple myeloma. Blood 2020; 136: 2656-2666
• 18 Scherer HU, van der Woude D, Ioan-Facsinay A. et al. Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum 2010; 62: 1620-1629
• 19 Bordron A, Morel M, Bagacean C. et al. Hyposialylation Must Be Considered to Develop Future Therapies in Autoimmune Diseases. Int J Mol Sci 2021; 22
• 20 Hauser B, Riches PL, Gilchrist T. et al. Autoantibodies to osteoprotegerin are associated with increased bone resorption in rheumatoid arthritis. Ann Rheum Dis 2015; 74: 1631-1632
• 21 Hauser B, Zhao S, Visconti MR. et al. Autoantibodies to Osteoprotegerin are Associated with Low Hip Bone Mineral Density and History of Fractures in Axial Spondyloarthritis: A Cross-Sectional Observational Study. Calcif Tissue Int 2017; 101: 375-383
• 22 Riches PL, McRorie E, Fraser WD. et al. Osteoporosis associated with neutralizing autoantibodies against osteoprotegerin. N Engl J Med 2009; 361: 1459-1465
• 23 Larussa T, Suraci E, Nazionale I. et al. No evidence of circulating autoantibodies against osteoprotegerin in patients with celiac disease. World J Gastroenterol 2012; 18: 1622-1627
• 24 Vaziri-Sani F, Brundin C, Agardh D. Osteoprotegerin autoantibodies do not predict low bone mineral density in middle-aged women. Bone Rep 2017; 7: 132-136
• 25 Jansen MA, Kiefte-de Jong JC, Gaillard R. et al. Growth trajectories and bone mineral density in anti-tissue transglutaminase antibody-positive children: the Generation R Study. Clin Gastroenterol Hepatol 2015; 13: 913-20 e5
• 26 Agardh D, Bjorck S, Agardh CD. et al. Coeliac disease-specific tissue transglutaminase autoantibodies are associated with osteoporosis and related fractures in middle-aged women. Scand J Gastroenterol 2009; 44: 571-578
• 27 Mousa A, Cui C, Song A. et al. Transglutaminases factor XIII-A and TG2 regulate resorption, adipogenesis and plasma fibronectin homeostasis in bone and bone marrow. Cell Death Differ 2017; 24: 844-854
• 28 Engdahl C, Bang H, Dietel K. et al. Periarticular Bone Loss in Arthritis Is Induced by Autoantibodies Against Citrullinated Vimentin. J Bone Miner Res 2017; 32: 1681-1691
• 29 Krishnamurthy A, Joshua V, Haj Hensvold A. 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
• 30 Kurowska W, Slowinska I, Krogulec Z. et al. Antibodies to Citrullinated Proteins (ACPA) Associate with Markers of Osteoclast Activation and Bone Destruction in the Bone Marrow of Patients with Rheumatoid Arthritis. J Clin Med 2021; 10
• 31 Llorente I, Merino L, Ortiz AM. et al. Anti-citrullinated protein antibodies are associated with decreased bone mineral density: baseline data from a register of early arthritis patients. Rheumatol Int 2017; 37: 799-806
• 32 Orsolini G, Caimmi C, Viapiana O. et al. Titer-Dependent Effect of Anti-Citrullinated Protein Antibodies On Systemic Bone Mass in Rheumatoid Arthritis Patients. Calcif Tissue Int 2017; 101: 17-23
• 33 Hecht C, Englbrecht M, Rech J. et al. Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann Rheum Dis 2015; 74: 2151-2156
• 34 Kleyer A, Finzel S, Rech J. et al. Bone loss before the clinical onset of rheumatoid arthritis in subjects with anticitrullinated protein antibodies. Ann Rheum Dis 2014; 73: 854-860
• 35 Regueiro C, Ortiz AM, Boveda MD. et al. Association of high titers of anti-carbamylated protein antibodies with decreased bone mineral density in early arthritis patients. PLoS One 2018; 13: e0202583
• 36 Shi J, Knevel R, Suwannalai P. et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl Acad Sci U S A 2011; 108: 17372-17377
• 37 Nijjar JS, Morton FR, Bang H. et al. The impact of autoantibodies against citrullinated, carbamylated, and acetylated peptides on radiographic progression in patients with new-onset rheumatoid arthritis: an observational cohort study. The Lancet Rheumatology 2021; 3: e284-e293
• 38 Panaroni C, Yee AJ, Raje NS. Myeloma and Bone Disease. Curr Osteoporos Rep 2017; 15: 483-498
• 39 Kavanagh N, Ryan EJ, Widaa A. et al. Staphylococcal Osteomyelitis: Disease Progression, Treatment Challenges, and Future Directions. Clin Microbiol Rev 2018; 31
• 40 Kamohara A, Hirata H, Xu X. et al. IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2. Int Immunol 2020; 32: 89-104
• 41 Breedveld AC, van Gool MMJ, van Delft MAM. et al. IgA Immune Complexes Induce Osteoclast-Mediated Bone Resorption. Front Immunol 2021; 12: 651049