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Beta-Cryptoxanthin Inhibits Lipopolysaccharide-Induced Osteoclast Differentiation and Bone Resorption via the Suppression of Inhibitor of NF-?B Kinase Activity.

ABSTRACT: Beta-cryptoxanthin (?-cry) is a typical carotenoid found abundantly in fruit and vegetables such as the Japanese mandarin orange, persimmon, papaya, paprika, and carrot, and exerts various biological activities (e.g., antioxidant effects). We previously reported that ?-cry suppressed lipopolysaccharide (LPS)-induced osteoclast differentiation via the inhibition of prostaglandin (PG) E? production in gingival fibroblasts and restored the alveolar bone loss in a mouse model for periodontitis in vivo. In this study, we investigated the molecular mechanism underlying the inhibitory effects of ?-cry on osteoclast differentiation. In mouse calvarial organ cultures, LPS-induced bone resorption was suppressed by ?-cry. In osteoblasts, ?-cry inhibited PGE? production via the downregulation of the LPS-induced mRNA expression of cyclooxygenase (COX)-2 and membrane-bound PGE synthase (mPGES)-1, which are PGE synthesis-related enzymes, leading to the suppression of receptor activator of NF-?B ligand (RANKL) mRNA transcriptional activation. In an in vitro assay, ?-cry directly suppressed the activity of the inhibitor of NF-?B kinase (IKK) ?, and adding ATP canceled this IKK? inhibition. Molecular docking simulation further suggested that ?-cry binds to the ATP-binding pocket of IKK?. In Raw264.7 cells, ?-cry suppressed RANKL-mediated osteoclastogenesis. The molecular mechanism underlying the involvement of ?-cry in LPS-induced bone resorption may involve the ATP-competing inhibition of IKK activity, resulting in the suppression of NF-?B signaling.

SUBMITTER: Hirata N

PROVIDER: S-EPMC6412436 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Beta-Cryptoxanthin Inhibits Lipopolysaccharide-Induced Osteoclast Differentiation and Bone Resorption via the Suppression of Inhibitor of NF-κB Kinase Activity.

Hirata Narumi N Ichimaru Ryota R Tominari Tsukasa T Matsumoto Chiho C Watanabe Kenta K Taniguchi Keita K Hirata Michiko M Ma Sihui S Suzuki Katsuhiko K Grundler Florian M W FMW Miyaura Chisato C Inada Masaki M

Nutrients 20190210 2

Beta-cryptoxanthin (β-cry) is a typical carotenoid found abundantly in fruit and vegetables such as the Japanese mandarin orange, persimmon, papaya, paprika, and carrot, and exerts various biological activities (e.g., antioxidant effects). We previously reported that β-cry suppressed lipopolysaccharide (LPS)-induced osteoclast differentiation via the inhibition of prostaglandin (PG) E₂ production in gingival fibroblasts and restored the alveolar bone loss in a mouse model for periodontitis in vi ...[more]

PMID: 30744180

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Project description:ObjectiveAutoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption.MethodsAnti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption.ResultsNET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts.ConclusionIgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.

Dataset Information

Beta-Cryptoxanthin Inhibits Lipopolysaccharide-Induced Osteoclast Differentiation and Bone Resorption via the Suppression of Inhibitor of NF-?B Kinase Activity.

Publications

Beta-Cryptoxanthin Inhibits Lipopolysaccharide-Induced Osteoclast Differentiation and Bone Resorption via the Suppression of Inhibitor of NF-κB Kinase Activity.

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