Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss

• Published in: Nature communications Vol. 6; no. 1; p. 6651
• Main Authors: Harre, Ulrike, Lang, Stefanie C., Pfeifle, René, Rombouts, Yoann, Frühbeißer, Sabine, Amara, Khaled, Bang, Holger, Lux, Anja, Koeleman, Carolien A., Baum, Wolfgang, Dietel, Katharina, Gröhn, Franziska, Malmström, Vivianne, Klareskog, Lars, Krönke, Gerhard, Kocijan, Roland, Nimmerjahn, Falk, Toes, René E. M., Herrmann, Martin, Scherer, Hans Ulrich, Schett, Georg
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.03.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13/1; 631/250/2152/2153; 631/250/249/1313; 64/60; 692/308; 692/698/690/292/797; 82/51; 82/58; Acids; Animals; Antigens; Arthritis, Experimental - diagnostic imaging; Arthritis, Experimental - immunology; Arthritis, Experimental - metabolism; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - metabolism; Bone and Bones - diagnostic imaging; Bone and Bones - immunology; Bone and Bones - metabolism; Bone Resorption - diagnostic imaging; Bone Resorption - immunology; Bone Resorption - metabolism; Cell Differentiation - immunology; Dendritic cells; Dynamic Light Scattering; Female; Galactose - metabolism; Glycosylation; Hexosamines - pharmacology; Humanities and Social Sciences; Humans; Immunoglobulin Fc Fragments - metabolism; Immunoglobulin G - immunology; Immunoglobulin G - metabolism; Immunoglobulins; Male; Medicin och hälsovetenskap; Mice; Middle Aged; multidisciplinary; N-Acetylneuraminic Acid - metabolism; Osteoclasts - cytology; Osteoclasts - immunology; Osteoclasts - metabolism; Proteins; Receptors, Fc - genetics; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid arthritis; Rheumatology; RNA, Messenger - metabolism; Science; Science (multidisciplinary); X-Ray Microtomography; Netherlands; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7651

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. The IgG sugar moiety modulates the binding of immune complexes to their Fcγ receptors resulting in pro- or anti-inflammatory response. This study shows that IgG sialylation also affects osteoclastogenesis and bone mass in mice and humans, identifying a new link between bone and the immune system.