AB0184 ROLE OF DENDRITIC CELLS IN ARTHRITIS AND OSTEOCLASTOGENESIS
Authors: A. Mazzucato-Puchner, E. Simader, V. Saferding, M. Hofmann, M. Kieler, R. Pfeifle, G. Krönke, J. S. Smolen, S. Hayer, G. Steiner, D. Aletaha, S. Blüml
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Dendritic cells are innate immune cells known for their role in antigen presentation and activation of the adaptive immune system. However, their role in the pathogenesis of inflammatory arthritis is poorly defined. <h3>Objectives:</h3> We aimed to elucidate the role of dendritic cells in models of inflammatory arthritis with special emphasis on inflammatory bone destruction. <h3>Methods:</h3> CD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored histologically. We measured cytokines in synovitis by quantitative polymerase chain reaction (qPCR). We performed ovariectomy in CD11cDTR mice treated with PBS or DT. We analysed CD11cDTR and Zbtb46-DTR-treated mice with DT using histomorphometry and OCs of CD11c and Zbtb46 fate reporter mice by fluorescent imaging. We sorted murine and human OC precursors and stimulated them with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) to generate OCs. <h3>Results:</h3> Targeting CD11c<sup>+</sup> cells in vivo in models of inflammatory arthritis (STA and hTNFtg) ameliorates arthritis by reducing inflammatory bone destruction and OC generation. Targeting CD11c-expressing cells in unchallenged mice removes all OCs in their long bones. We demonstrate that OCs are derived from CD11c<sup>+</sup> cells and from Zbtb46<sup>+</sup> conventional dendritic cells (cDCs) as all OCs in CD11c-Tomato and Zbtb46-Tomato fate reporter mice are Tomato<sup>+</sup>. In line, administration of DT in Zbtb46-DTR mice depletes all OCs in long bones. Finally, human CD1c-expressing cDCs readily differentiated into bone resorbing OCs. <h3>Conclusion:</h3> Taken together, we identify DCs as important OC precursors in bone homeostasis and inflammation, and targeting them might open new avenues for therapeutic interventions in OC-mediated diseases. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Antonia Mazzucato-Puchner: None declared, Elisabeth Simader Lilly, Abbvie, Victoria Saferding Janssen, Melanie Hofmann: None declared, Markus Kieler: None declared, Rene Pfeifle: None declared, Gerhard Krönke: None declared, Josef S. Smolen speakers' bureau for Samsung, Lilly, R-Pharm, Chugai, MSD, Janssen, Novartis-Sandoz; consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; participation on a data safety monitoring/advisory board for AstraZeneca., grants from AbbVie, Astra-Zeneca, Lilly and Galapagos;, Silvia Hayer: None declared, Günter Steiner reports about speakers' bureau from Thermo Fisher Scientific, Daniel Aletaha reports about speakers' bureau from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, and Sandoz, Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, and Sandoz, grants from Abbvie, Amgen, Galapagos, Lilly, and Sanofi;, Stephan Blüml: None declared.