title: Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss.
abstract: Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone loss.
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Harre
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Stefanie C
authors.initials: SC
authors.lastname: Lang
authors.affiliation: 1] Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany [2] Nikolaus Fiebiger Center of Molecular Medicine, University of Erlangen- Nuremberg, Erlangen 91054, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Pfeifle
authors.affiliation: 1] Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands [2] Center of Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Rombouts
authors.affiliation: Department of Chemistry and Pharmacy, Interdisciplinary Center for Molecular Materials (ICMM), University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Frühbeißer
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, Solna 17177, Sweden.
authors.forename: Khaled
authors.initials: K
authors.lastname: Amara
authors.affiliation: Orgentec Diagnostika, Mainz 55129, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Bang
authors.affiliation: Department of Genetics, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Lux
authors.affiliation: 1] Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands [2] Center of Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
authors.forename: Carolien A
authors.initials: CA
authors.lastname: Koeleman
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dietel
authors.affiliation: Department of Chemistry and Pharmacy, Interdisciplinary Center for Molecular Materials (ICMM), University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Gröhn
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, Solna 17177, Sweden.
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institute and Karolinska University Hospital, Solna 17177, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: 1] Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany [2] Nikolaus Fiebiger Center of Molecular Medicine, University of Erlangen- Nuremberg, Erlangen 91054, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Kocijan
authors.affiliation: Department of Genetics, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Herrmann
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Scherer
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D000067493:Dynamic Light Scattering; D005260:Female; D005690:Galactose / Q000378:metabolism; D006031:Glycosylation; D006595:Hexosamines / Q000494:pharmacology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D011961:Receptors, Fc / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D006595:Hexosamines; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D012333:RNA, Messenger; D011961:Receptors, Fc; D019158:N-Acetylneuraminic Acid; D005690:Galactose; C002022:N-acetylmannosamine
references.citation: Arthritis Rheum. 2003 Oct;48(10):2741-9
references.pmid: 14558078
references.citation: Biochim Biophys Acta. 2006 Apr;1760(4):693-700
references.pmid: 16343775
references.citation: Nature. 2004 Apr 15;428(6984):758-63
references.pmid: 15085135
references.citation: J Clin Invest. 1973 May;52(5):1282-8
references.pmid: 4700496
references.citation: Arthritis Rheum. 1992 Oct;35(10):1126-33
references.pmid: 1418003
references.citation: Ann Rheum Dis. 1995 May;54(5):382-5
references.pmid: 7794045
references.citation: Science. 1999 May 21;284(5418):1372-6
references.pmid: 10334995
references.citation: J Clin Endocrinol Metab. 2005 Dec;90(12):6508-15
references.pmid: 16189253
references.citation: Arthritis Res Ther. 2006;8(3):R64
references.pmid: 16569263
references.citation: Science. 2006 Aug 4;313(5787):670-3
references.pmid: 16888140
references.citation: Mol Immunol. 2007 Mar;44(7):1524-34
references.pmid: 17045339
references.citation: Biochim Biophys Acta. 2007 Feb;1770(2):297-306
references.pmid: 17110045
references.citation: Annu Rev Immunol. 2007;25:21-50
references.pmid: 17029568
references.citation: J Clin Invest. 2007 Jun;117(6):1585-94
references.pmid: 17549255
references.citation: Science. 2008 Apr 18;320(5874):373-6
references.pmid: 18420934
references.citation: J Clin Invest. 2012 May;122(5):1791-802
references.pmid: 22505457
references.citation: J Proteomics. 2012 Feb 2;75(4):1318-29
references.pmid: 22120122
references.citation: Semin Immunopathol. 2012 May;34(3):443-53
references.pmid: 22437760
references.citation: Autoimmunity. 2012 Dec;45(8):612-9
references.pmid: 22978425
references.citation: Ann Rheum Dis. 2013 Feb;72(2):278-85
references.pmid: 22918932
references.citation: Rheumatol Int. 2013 Feb;33(2):451-6
references.pmid: 22457007
references.citation: Curr Opin Organ Transplant. 2011 Feb;16(1):7-14
references.pmid: 21150612
references.citation: J Exp Med. 2013 Mar 11;210(3):445-55
references.pmid: 23440041
references.citation: J Mol Biol. 2013 Apr 26;425(8):1253-8
references.pmid: 23416198
references.citation: J Immunol. 2013 Apr 15;190(8):4315-23
references.pmid: 23509345
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9868-72
references.pmid: 23697368
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10729-34
references.pmid: 23754379
references.citation: Rheumatology (Oxford). 2013 Sep;52(9):1572-82
references.pmid: 23681398
references.citation: J Allergy Clin Immunol. 2014 Mar;133(3):853-63.e5
references.pmid: 24210883
references.citation: Ann Rheum Dis. 2014 May;73(5):854-60
references.pmid: 23520034
references.citation: J Immunol. 2014 Jun 1;192(11):5031-8
references.pmid: 24760152
references.citation: Arthritis Rheum. 2004 Mar;50(3):709-15
references.pmid: 15022309
references.citation: Immunity. 2002 Feb;16(2):157-68
references.pmid: 11869678
references.citation: Arthritis Res Ther. 2008;10(4):R94
references.pmid: 18710572
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19571-8
references.pmid: 19036920
references.citation: Arthritis Rheum. 2010 Jun;62(6):1620-9
references.pmid: 20178128
references.citation: Arthritis Res Ther. 2010;12(4):R132
references.pmid: 20609218
references.citation: Arthritis Rheum. 2011 Dec;63(12):3897-907
references.pmid: 22127707
references.citation: Arthritis Res Ther. 2011;13(4):234
references.pmid: 21861861
references.citation: Arthritis Res Ther. 2011;13(4):235
references.pmid: 21861862
references.citation: Nature. 2012 May 3;485(7396):69-74
references.pmid: 22522930