IL‐23 promotes osteoclast formation by up‐regulation of receptor activator of NF‐κB (RANK) expression in myeloid precursor cells

Abstract

Inflammation-mediated bone loss is a major feature of various bone diseases including rheumatoid arthritis, osteoarthritis and advanced periodontitis. Enhanced osteoclast development or activity at the inflammation site results in bone resorption. IL-23 is a heterodimeric cytokine belonging to the IL-6/IL-12 family that has been implicated in the pathogenesis of rheumatoid arthritis and demonstrated to play a role in osteoclastogenesis via stimulation of IL-17 production. In this study we investigated whether IL-23 contributes to the regulation of osteoclast differentiation independent of the IL-17 pathway. We show that IL-23 dose-dependently up-regulates receptor activator of NF-jB expression in primary murine bone marrow macrophages and RAW264.7 cells and thereby promotes commitment of myeloid precursor cells to receptor activator of NF-jB ligand-mediated osteoclastic differentiation. However, IL-23 by itself is insufficient to induce osteoclastogenesis. Increased osteoclastic differentiation of cells was associated with enhanced cathepsin K expression and dentine resorption indicating enhanced formation of functional osteoclasts. IL-17 was not detectable in culture supernatants and when added to cultures, did not promote differentiation of RAW264.7 cells. These results demonstrate that IL-23 can act directly on myeloid precursor cells in addition to indirectly stimulating receptor activator of NF-jB ligand production in osteoblasts and explains its potency in driving osteoclast development in inflammation-mediated bone pathology.Key words: Bone resorption . IL-23 . Inflammation . Osteoclast Supporting Information available online IntroductionBone loss associated with chronic inflammation and infection such as in rheumatoid arthritis or periodontitis is due to an imbalance in bone remodelling that favours resorption. In most instances, low bone mass is the consequence of an increase in osteoclast number or excess osteoclastic activity [1][2][3]. Macrophage colony-stimulation factor-1 (M-CSF) and receptor activator of NF-kB ligand (RANKL) are essential cytokines for osteoclast development [4,5]. M-CSF is produced primarily by stromal fibroblasts, osteoblasts and activated T cells and mediates the survival and proliferation of monocyte/macrophage precursors [6,7]. c-Fms is the sole receptor for M-CSF [8]. c-Fms deficient mice develop an osteoclast/macrophage deficiency and associated osteopetrosis [9], indicating an important role for M-CSF in regulation of bone homeostasis. RANKL is a TNF family cytokine produced by activated T cells, which mediates dendritic cell activation [10,11]. However, this cytokine also plays a central role in bone remodelling. Bone marrow stromal cells and osteoblasts produce RANKL and thereby promote osteoclast formation [12], which ties bone resorption to bone synthesis. Activation of receptor actovator of NF kB (RANKL), the receptor for RANKL, commits myeloid precursors to the osteoclast fate [13]. Osteoprotegerin has been identified as a decoy receptor that competes with RANK for ...

Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways

“…(39,49) Our results show that MA markedly inhibits the association of RANK with TRAF6 and that MA downregulates M-CSF-induced RANK expression, suggesting that MA inhibits NF-kB activation and osteoclastogenesis at the early stage by modulating the expression of RANK and its recruitment of TRAF6. NFATc1 can regulate the expression of a number of genes associated with osteoclast differentiation and function, such as TRAcP, latent transforming growth factor b-binding protein3 (LTBP3), chloride channel (ClC7), MMP9, CTR, cathepsin K, and c-Src.…”

In vitro study of inhibitory millimeter wave treatment effects on the TNF-α-induced NF-κB signal transduction pathway

“…The phosphorylation and ubiquitination events alter the configuration of IκB, which is consequently degraded by ATPdependent 26S proteasomes, exposing the nuclear localization signal of the NF-κB (Rel) protein. This activation of NF-κB causes its rapid intranuclear translocation and binding to the κB sites of the target genes, thus controling the transcription and expression of multiple genes involved in inflammatory and immune responses, as well as cellular proliferation, differentiation and apoptosis (10,11). The millimeter wave is a high-frequency electromagnetic wave.…”

Induction of osteoclast progenitors in inflammatory conditions: key to bone destruction in arthritis

“…Some potent arthritic mediators exert their effects in synergy with IL-17, such as IL-23, which is able to elicit severe arthritis with a profound bone-resorptive phenotype. It enhances osteoclast differentiation by upregulating RANK expression in peripheral blood OCPs [69]. IL-32, induced by IL-17, stimulates TNF-α and IL-1β production, and promotes maturation of OCPs independently of RANKL [70] Other cytokines contribute to the pathology of arthritis mainly by increasing RANKL expression in CD4 + T lymphocytes or synovial fibroblasts.…”