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Abstract Background Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging. Methods Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts. Results The JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions. Conclusions This is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.

Interleukin (IL)-35 is an immunosuppressive cytokine mainly produced by regulatory T cells. IL-35 mediates immunological functions by suppressing the inflammatory immune response. However, the role of IL-35 in bone-destructive diseases remains unclear, especially in terms of osteoclastogenesis. Therefore, the current study investigated the synergistic effect of IL-35 on osteoclastogenesis that is involved the pathogeneses of periodontitis and rheumatoid arthritis. Osteoclastic differentiation and osteoclastogenesis of RAW264 (RAW) cells induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) and IL-35 were evaluated by tartrate-resistant acid phosphate staining, hydroxyapatite resorption assays, and quantitative polymerase chain reaction. The effect of IL-35 on RANKL-stimulated signaling pathways was assessed by Western blot analysis. Costimulation of RAW cells by RANKL and IL-35 induced osteoclastogenesis significantly compared with stimulation by RANKL alone. Phosphorylations of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase tended to be increased by RANKL and IL-35 compared with RANKL or IL-35 alone. Additionally, the osteoclastogenesis induced by RANKL and IL-35 was suppressed by inhibition of ERK. In this study, IL-35 and RANKL induced osteoclastogenesis synergistically. Previous reports have shown that IL-35 suppresses the differentiation of osteoclasts. Therefore, IL-35 might play dual roles of destruction and protection in osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Inflammation-induced bone erosion is a major pathological factor in several chronic inflammatory diseases that often cause severe outcomes, such as rheumatoid arthritis and periodontitis. Plenty of evidences indicated that the inflammatory bone destruction was attributed to an increase in the number of bone-resorbing osteoclasts. However, anti-resorptive therapy alone failed to prevent bone loss in an inflammatory condition. Conventional anti-inflammation treatments are usually intended to suppress inflammation only, but ignore debilitating the subsequent bone destruction. Therefore, inhibition of proinflammatory activation of osteoclastogenesis could be an important strategy for the development of drugs aimed at preventing inflammatory bone destruction. Methods: In this study, we synthesized a peptide coated gold cluster to evaluate its effects on inflammatory osteoclastogenesis in vitro and inflammation-induced bone destruction in vivo . The in vitro anti-inflammation and anti-osteoclastogenesis effects of the cluster were evaluated in LPS-stimulated and receptor activator of nuclear factor κB ligand (RANKL) stimulated macrophages, respectively. The LPS-induced expression of crucial pro-inflammation cytokines and RANKL-induced osteoclastogenesis as well as the activation of NF-κB pathway in both situations were detected. The inflammation-induced RANKL expression and subsequent inflammatory bone destruction in vivo were determined in collagen-immunized mice. Results: The gold cluster strongly suppresses RANKL-induced osteoclast formation via inhibiting the activation of NF-κB pathway in vitro . Moreover, treatment with the clusters at a dose of 5 mg Au/kg.bw significantly reduces the severity of inflammation-induced bone and cartilage destruction in vivo without any significant toxicity effects. Conclusion: Therefore, the gold clusters may offer a novel potent therapeutic stratagem for inhibiting chronic inflammation associated bone destruction., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.