The Dectin 1 Agonist Curdlan Regulates Osteoclastogenesis by Inhibiting Nuclear Factor of Activated T cells Cytoplasmic 1 (NFATc1) through Syk Kinase

Yamasaki, Toru; Ariyoshi, Wataru; Okinaga, Toshinori; Adachi, Yoshiyuki; Hosokawa, Ryuji; Mochizuki, Seibu; Sakurai, Kazuo; Nishihara, Tatsuji

doi:10.1074/jbc.m114.551416

Cited by 28 publications

(28 citation statements)

References 63 publications

(57 reference statements)

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“…β-1-3-glucans are agonist ligands of dectin-1 and present on the cell wall of various fungal pathogens, such as Candida albicans [ 15 – 17 ]. Previous studies indicate that the dectin-1 agonist curdlan suppresses RANKL-induced osteoclastogenesis [ 18 ]. However, the mechanisms underlying its anti-osteoclastogenic effects need to be further elucidated.…”

Section: Introductionmentioning

confidence: 99%

Dectin-1 signaling inhibits osteoclastogenesis via IL-33-induced inhibition of NFATc1

et al. 2017

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Abnormal osteoclast activation contributes to osteolytic bone diseases (OBDs). It was reported that curdlan, an agonist of dectin-1, inhibits osteoclastogenesis. However, the underlying mechanisms are not fully elucidated. In this study, we found that curdlan potently inhibited RANKL-induced osteoclast differentiation and the resultant bone resorption. Curdlan inhibited the expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), the key transcriptional factor for osteoclastogenesis. Notably, dectin-1 activation increased the expression of MafB, an inhibitor of NFATc1, and IL-33 in osteoclast precursors. Mechanistic studies revealed that IL-33 enhanced the expression of MafB in osteoclast precursors and inhibited osteoclast precursors to differentiate into mature osteoclasts. Furthermore, blocking ST2, the IL-33 receptor, partially abrogated curdlan-induced inhibition of NFATc1 expression and osteoclast differentiation. Thus, our study has provided new insights into the mechanisms of dectin-1-induced inhibition of osteoclastogenesis and may provide new targets for the therapy of OBDs.

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Section: Introductionmentioning

confidence: 99%

Dectin-1 signaling inhibits osteoclastogenesis via IL-33-induced inhibition of NFATc1

et al. 2017

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“…1B). As resveratrol and piceatannol are reported to have anti-osteoclastogenic activities (31,32) and dRG exhibited potent anti-osteoclastogenic activity, the present study further investigated the anti-osteoclastogenic effect of dRG.…”

Section: Resultsmentioning

confidence: 99%

Desoxyrhapontigenin inhibits RANKL‑induced osteoclast formation and prevents inflammation‑mediated bone loss

et al. 2018

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Desoxyrhapontigenin (DRG), a stilbene compound from Rheum undulatum, has been found to exhibit various pharmacological activities, however, its impact on osteoclast formation has not been investigated. The present study investigated the effect of DRG on receptor activator of nuclear factor‑κB ligand (RANKL)‑induced osteoclast differentiation in mouse bone marrow macrophages (BMMs) and inflammation‑induced bone loss in vivo. BMMs or RAW264.7 cells were treated with DRG, followed by an evaluation of cell viability, RANKL‑induced osteoclast differentiation, actin‑ring formation and resorption pits activity. The effects of DRG on the RANKL‑induced phosphorylation of MAPK and the expression of nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and c‑Fos were evaluated using western blot analysis once the BMMs were exposed to RANKL and DRG. The expression levels of osteoclast marker genes were also evaluated using western blot analysis and reverse transcription‑quantitative polymerase chain reaction A lipopolysaccharide (LPS)‑induced murine bone loss model was used to evaluate the protective effect of DRG on inflammation‑induced bone‑loss. The results demonstrated that DRG suppressed the RANKL‑induced differentiation of BMMs into osteoclasts, osteoclast actin‑ring formation and bone resorption activity in a dose‑dependent manner. Furthermore, DRG significantly inhibited LPS‑induced bone loss in a mouse model. At the molecular level, DRG inhibited the RANKL‑induced activation of extracellular signal‑regulated kinase, the expression of c‑Fos, and the induction of NFATc1, a crucial transcription factor for osteoclast formation. DRG decreased the expression levels of osteoclast marker genes, including matrix metalloproteinase‑9, tartrate‑resistant acid phosphatase and cathepsin K. In conclusion, these findings suggested that DRG inhibited the differentiation of BMMs into mature osteoclasts by suppressing the RANKL‑induced activator protein‑1 and NFATc1 signaling pathways, and may be a potential candidate for treating and/or preventing osteoclast‑associated diseases, including osteoporosis.

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“…TAS05567 Suppresses Development of TRAP-Positive Multinucleated Cells. In addition to its crucial role in inflammation, Syk contributes directly to bone resorption in RA via its kinase activity-mediated regulation of receptor activator of nuclear factor kB (RANK) signaling pathway that is essential for differentiation and activation of osteoclasts (Yamasaki et al, 2014). Therefore, we explored the effect of TAS05567 on osteoclast differentiation using human osteoclast precursor cells.…”

Section: Resultsmentioning

confidence: 99%

TAS05567, a Novel Potent and Selective Spleen Tyrosine Kinase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models

Hayashi

Kaneko

Demizu

et al. 2018

J Pharmacol Exp Ther

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Spleen tyrosine kinase (Syk) is involved in regulation of B-cell receptor (BCR) and Fc receptor downstream signal pathways. Syk plays an essential role in production of inflammatory mediators and differentiation in various immune cells and is therefore an attractive target for treating inflammatory conditions, such as autoimmune and allergic diseases. We identified TAS05567 as a highly selective Syk inhibitor and evaluated its therapeutic potential in animal models. In vitro biochemical assays were performed with available kinase assay panels. Inhibitory effects of TAS05567 on immune cells were analyzed by assessing the Syk downstream signaling pathway and production of inflammatory factors. In vivo effects of TAS05567 were evaluated in animal models of autoimmune diseases and antigen-specific IgE transgenic mice. TAS05567 inhibited only 4 of 191 kinases tested but inhibited Syk enzymatic activity with high potency. TAS05567 inhibited BCR-dependent signal transduction in Ramos cells, FcR-mediated tumor necrosis factor- production in THP-1 cells, and FcR-mediated histamine release from RBL-2H3 cells. In rheumatoid arthritis models, TAS05567 suppressed hind-paw swelling in a dose-dependent manner compared with vehicle. Moreover, TAS05667 markedly reduced histopathologic scores in an established rat arthritis model. In a mouse immune thrombocytopenic purpura model, platelet counts were reduced with injection of anti-platelet antibody. TAS05567 prevented the platelet count decrease in a dose-dependent manner. Finally, TAS05567 treatment suppressed IgE-mediated ear swelling in vivo. Collectively, our data indicate TAS05567 is a selective Syk inhibitor and potential therapeutic candidate for treating humoral immune-mediated inflammatory conditions such as autoimmune and allergic diseases.

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The Dectin 1 Agonist Curdlan Regulates Osteoclastogenesis by Inhibiting Nuclear Factor of Activated T cells Cytoplasmic 1 (NFATc1) through Syk Kinase

Cited by 28 publications

References 63 publications

Dectin-1 signaling inhibits osteoclastogenesis via IL-33-induced inhibition of NFATc1

Dectin-1 signaling inhibits osteoclastogenesis via IL-33-induced inhibition of NFATc1

Desoxyrhapontigenin inhibits RANKL‑induced osteoclast formation and prevents inflammation‑mediated bone loss

TAS05567, a Novel Potent and Selective Spleen Tyrosine Kinase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models

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