Mechanisms involved in regulation of osteoclastogenesis by glucan through autophagy

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K09797
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kyushu Dental College
• Principal Investigator: Ariyoshi Wataru 九州歯科大学, 歯学部, 教授 (40405551)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 破骨細胞 / β-glucan / dectin-1 / オートファジー / ユビキチン/プロテアソームシステム / spleen tyrosine kinas / nuclear factor-kappa B / Irf-8

Outline of Final Research Achievements

In this study, we evaluated the bioactivity of several β‐glucans on receptor activator of nuclear factor‐kappa B ligand (RANKL)‐induced osteoclastogenesis and observed that some β‐glucan inhibited this process in mouse bone marrow cells and dectin‐1-overexpressing RAW264.7 cells.
β-glucan binds to dectin‐1 expressed on osteoclast precursors and attenuates RANKL‐induced osteoclast differentiation by down-regulating nuclear factor of activated T cell c1 (NFATc1) activation. Moreover, we found that the inhibition of NFATc1 activation by β-glucan is dependent on the (1) suppression of NF‐κB cascade, (2) stimulation of interferon regulatory factor 8 (Irf‐8), negative regulators of osteoclastogenesis by up-regulating their transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp 1), and (3) down-regulation of the Spleen tyrosine kinase (Syk)‐mediated signaling by degrading Syk protein via autophagy and the ubiquitin/proteasome system.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

破骨細胞前駆細胞上に特異的に発現するβ-glucan認識受容体であるdectin-1に注目し、研究を展開した結果、dectin-1受容体に結合したβ-glucanが、オートファジーなどを介して破骨細胞分化を抑制することを見出した。このことから、β-glucanは、将来的に臨床応用可能な、選択性の高い骨代謝治療薬の開発に極めて有効であると考える。さらに、当該研究で得られた知見は、骨代謝疾患に対する新たな治療戦略確立に向けての展開にとどまらず、骨代謝制御機構の免疫学的アプローチによる解析を通じて、数多く存在する骨と免疫系とが関わる疾患の病態生理の解明にも寄与するものと期待される。