title: The dectin 1 agonist curdlan regulates osteoclastogenesis by inhibiting nuclear factor of activated T cells cytoplasmic 1 (NFATc1) through Syk kinase.
abstract: Several immune system cell surface receptors are reported to be associated with osteoclastogenesis. Dectin 1, a lectin receptor for β-glucan, is found predominantly on cells of the myeloid lineage. In this study, we examined the effect of the dectin 1 agonist curdlan on osteoclastogenesis. In mouse bone marrow cells and dectin 1-overexpressing RAW 264.7 cells (d-RAWs), curdlan suppressed receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation, bone resorption, and actin ring formation in a dose-dependent manner. This was achieved within non-growth inhibitory concentrations at the early stage. Conversely, curdlan had no effect on macrophage colony-stimulating factor-induced differentiation. Furthermore, curdlan inhibited RANKL-induced nuclear factor of activated T cell cytoplasmic 1 (NFATc1) expression, thereby decreasing osteoclastogenesis-related marker gene expression, including tartrate-resistant acid phosphatase, osteoclast stimulatory transmembrane protein, cathepsin K, and matrix metallopeptidase 9. Curdlan inhibited RANKL-induced c-fos expression, followed by suppression of NFATc1 autoamplification, without significantly affecting the NF-κB signaling pathway. We also observed that curdlan treatment decreased Syk protein in d-RAWs. Inhibition of the dectin 1-Syk kinase pathway by Syk-specific siRNA or chemical inhibitors suppressed osteoclast formation and NFATc1 expression stimulated by RANKL. In conclusion, our results demonstrate that curdlan potentially inhibits osteoclast differentiation, especially NFATc1 expression, and that Syk kinase plays a crucial role in the transcriptional pathways. This suggests that the activation of dectin 1-Syk kinase interaction critically regulates the genes required for osteoclastogenesis.
authors.affiliation: From the Division of Infections and Molecular Biology, Department of Health Promotion, Division of Oral Reconstruction and Rehabilitation, Department of Oral Functions, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: From the Division of Infections and Molecular Biology, Department of Health Promotion, arikichi@kyu-dent.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ariyoshi
authors.affiliation: From the Division of Infections and Molecular Biology, Department of Health Promotion.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Okinaga
authors.affiliation: the Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan, and.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Division of Oral Reconstruction and Rehabilitation, Department of Oral Functions, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hosokawa
authors.affiliation: the Department of Chemistry and Biochemistry, The University of Kitakyushu, Kitakyushu, Fukuoka 808-0135, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mochizuki
authors.affiliation: the Department of Chemistry and Biochemistry, The University of Kitakyushu, Kitakyushu, Fukuoka 808-0135, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sakurai
authors.affiliation: From the Division of Infections and Molecular Biology, Department of Health Promotion.
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Nishihara
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D037181:Lectins, C-Type / Q000819:agonists* / Q000378:metabolism; D008297:Male; D051379:Mice; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D000072377:Syk Kinase; D047071:beta-Glucans / Q000737:chemistry / Q000494:pharmacology*; D000099181:Dectin-1
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D050778:NFATC Transcription Factors; D011505:Protein-Tyrosine Kinases; D053245:RANK Ligand; D000072377:Syk Kinase; D047071:beta-Glucans; D000099181:Dectin-1; C038459:curdlan; C000606897:Syk protein, mouse
keywords: Bone Marrow; Curdlan; Dectin 1; Differentiation; NFAT Transcription Factor; Nuclear Translocation; Osteoclast; Pattern Recognition Receptor (PRR); Syk; c-fos