Interleukin-23 Regulates Inflammatory Osteoclastogenesis via Activation of CLEC5A(+) Osteoclast Precursors.

Abstract

To investigate the role of interleukin-23 (IL-23) in pathologic bone remodeling in inflammatory arthritis. In this study we investigated the role of IL-23 in osteoclast differentiation and activation using in vivo gene transfer techniques in wild-type and myeloid DNAX-activation protein 12-associating lectin-1 (MDL-1)-deficient mice, and by performing in vitro and in vivo osteoclastogenesis assays using spectral flow cytometry, micro-computed tomography analysis, Western blotting, and immunoprecipitation. Herein, we show that IL-23 induces the expansion of a myeloid osteoclast precursor population and supports osteoclastogenesis and bone resorption in inflammatory arthritis. Genetic ablation of C-type lectin domain family member 5A, also known as MDL-1, prevents the induction of osteoclast precursors by IL-23 that is associated with bone destruction, as commonly observed in inflammatory arthritis. Moreover, osteoclasts derived from the bone marrow of MDL-1-deficient mice showed impaired osteoclastogenesis, and MDL-1-/- mice had increased bone mineral density. Our data show that IL-23 signaling regulates the availability of osteoclast precursors in inflammatory arthritis that could be effectively targeted for the treatment of inflammatory bone loss in inflammatory arthritis.