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08.14 IL-23 receptor signalling is critical in normal bone remodelling and influences osteoclast activity in vitro and t cell-driven inflammatory bone damage in vivo
  1. Wida Razawy1,2,
  2. Patrick S Asmawidjaja1,2,
  3. Adriana MC Mus1,2,
  4. Marijke Schreuders-Koedam3,
  5. Marlieke Molendijk1,2,
  6. Mohamed Oukka4,
  7. Vijay K Kuchroo5,6,
  8. Bram CJ van der Eerden3,
  9. Erik Lubberts1,2
  1. 1Department of Rheumatology, Erasmus Medical Centre, Rotterdam, The Netherlands
  2. 2Department of Immunology, Erasmus Medical Centre, Rotterdam, The Netherlands
  3. 3Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
  4. 4Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, USA
  5. 5Evergrande Centre for Immunologic Diseases and Ann Romney Centre for Neurologic diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, USA
  6. 6The Broad Institute of MIT and Harvard, Cambridge, USA

Abstract

Background The interleukin (IL)−23/IL-17A immune pathway is critical for the development of autoimmune arthritis. Moreover, systemic exposure of IL-23 induced chronic arthritis, increased osteoclast differentiation and systemic bone loss in mice. However, the role of IL-23 on normal and pathologic bone remodelling is not fully elucidated.

We studied the role of IL-23R signalling on normal bone phenotype and bone damage during a T cell-mediated inflammatory arthritis in vivo and osteoclast differentiation and activity in vitro.

Materials and methods For antigen-induced arthritis (AIA), WT and IL-23RGFP+/GFP+ (IL-23R/-) mice were immunised with methylated bovine serum albumin (mBSA) in supplemented Complete Freund’s Adjuvant. After 7 days mice were injected in the knee joints with mBSA. Mice were macroscopically scored at given time points and knees were used for histological analysis.

Naïve WT and IL-23R/- bone marrow cells (BM) were cultured towards osteoclasts with MCSF, RANKL and +/- IL-23 and assessed for tartrate-resistant acid phosphatase (TRAP) staining, qPCRs and bone resorption. Femurs were used for MicroCT analysis and three-point bending test.

Results During AIA the onset of disease was not prevented in IL-23R-/- mice. However, the progression of arthritis was diminished, resulting in significantly less disease. Histological analysis revealed significantly less inflammation-mediated bone damage in knees of IL-23R/- versus WT mice.

In vitro, IL-23 had no direct effect on the number of TRAP+ cells, but increased bone resorption by osteoclasts. Interestingly, microCT data revealed a low bone mass phenotype in IL-23R-/- mice, with lower trabecular bone volume fraction, thickness and number as well as lower cortical volume and thickness. Preliminary three-point bending data show significantly reduced maximum force in IL-23RKO femurs.

Conclusions In vitro, IL-23 is involved in the activation of osteoclasts. Whereas T cell-driven inflammatory bone erosion is IL-23R signalling mediated, during normal bone remodelling IL-23R signalling is important for the maintenance of bone mass.

Keywords
  • Rheumatoid arthritis
  • IL-23R
  • antigen-induced arthritis
  • osteoclasts
  • bone damage

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