IL-23 Induces Receptor Activator of NF-κB Ligand Expression on CD4+ T Cells and Promotes Osteoclastogenesis in an Autoimmune Arthritis Model

Abstract

IL-23, a clinically novel cytokine, targets CD4+ T cells. Recent IL-1Ra−/− mouse studies have demonstrated that IL-23 indirectly stimulates the differentiation of osteoclast precursors by enhancing IL-17 release from CD4+ T cells. IL-17, in turn, stimulates osteoclastogenesis in osteoclast precursor cells. In this study, we found that IL-23 up-regulates receptor activator of NF-κB ligand expression by CD4+ T cells, and thus contributes to osteoclastogenesis. This indirect pathway is mediated by NF-κB and STAT3. We have also demonstrated that IL-23 can influence osteoclastogenesis positively under the special conditions in the IL-1-dominant milieu of IL-1Ra−/− mice. We propose that IL-23-enhanced osteoclastogenesis is mediated mainly by CD4+ T cells. The results of this study show that IL-23 is a promising therapeutic target for the treatment of arthritis-associated bone destruction.

Effects of inflammatory and anti‐inflammatory cytokines on the bone

“…It, thereby, acts in similar fashion as IL-12 another cytokine expressed by dendritic cells [46,47]. This direct effect of IL-23 may outweigh the indirect effect through polarizing T cells into the TH17 lineage [48].…”

Phosphatidylserine-containing liposomes suppress inflammatory bone loss by ameliorating the cytokine imbalance provoked by infiltrated macrophages

“…First, PSLs decreased the expression levels of IL-1b and IL-17, which can promote the expression of RANKL. 38,39 Second, PSL-induced IL-10, which strongly inhibited the expression of RANKL/RANK. 23,37 Third, PSLs are phagocytosed by the osteoclast precursor to directly decrease the expression of RANK by osteoclast precursor and the production of RANKL in cultured rat bone marrow cells.…”

Interleukin‐21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen‐induced arthritis

“…Mouse joint tissue and RA synovium were fixed in 4% paraformaldehyde, decalcified in EDTA bone decalcifier, embedded in paraffin, and sectioned as described previously (17). The sections were stained with hematoxylin and eosin, Safranin O, and toluidine blue to detect proteoglycans.…”

“…Bone marrowderived monocyte/macrophages were isolated as described previously (17). Osteoclast precursor cells (1 ϫ 10 5 /well) were further cultured onto 48-well plates in the presence of 10 ng/ml recombinant human M-CSF, 100 ng/ml soluble RANKL (sRANKL; PeproTech), or various concentrations of IL-21 for 4 days to generate osteoclasts.…”