Elucidation of the mechanism of osteoblast fate regulation by single cell analysis and search for target molecules of novel osteogenesis-promoting agents

• Project/Area Number: 17K11613
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Morphological basic dentistry
• Research Institution: International University of Health and Welfare
• Principal Investigator: Yoshioka Hirotaka 国際医療福祉大学, 医学部, 講師 (50523411)
• Co-Investigator(Kenkyū-buntansha): 吉子 裕二 広島大学, 医系科学研究科(歯), 教授 (20263709)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 骨芽細胞 / 単一細胞解析 / 骨代謝 / 細胞・組織 / 発生・分化

Outline of Final Research Achievements

Transcriptomes were obtained from single osteoblasts in order to follow the fluctuations in gene expression during osteoblast differentiation and to identify key regulatory mechanisms that determine the fate of osteoblasts. Machine learning analysis revealed heterogeneity of osteoblasts, and gene expression profiles during differentiation of osteoblasts into young osteocytes. We also found osteoblasts that may have retained or reacquired stem/progenitor cell characteristics. Taken together, the heterogeneity of osteoblasts may underlie the diversity of their function and developmental fate.

Academic Significance and Societal Importance of the Research Achievements

本研究により明らかとなった「骨芽細胞の分化に伴う遺伝子発現プロファイル」は，骨芽細胞の次なる運命を決定する制御機構の解明に向けた分子基盤となる。近年，遺伝子の発現をコントロールできる小分子化合物が見出され，転写制御からアプローチする創薬が注目されている。同様の原理に基づき，「骨芽細胞の運命を制御することにより骨代謝を改善し，骨形成を促進できる」と考えている。本研究により得られた知見が，骨の再生および骨関連疾患への臨床応用を見越したゲノム創薬や分子標的療法への足がかりとなる。

Research Products

• [Int'l Joint Research] University of Toronto(カナダ)
• [Int'l Joint Research] Institut de Cancerologie de l'Ouest(フランス)
• [Int'l Joint Research] University of Toronto(カナダ)
• [Int'l Joint Research] Institut de Cancerologie de l'Ouest(フランス)
• [Journal Article] Single‐cell RNA‐sequencing reveals the breadth of osteoblast heterogeneity (2021)
  • Author(s): Yoshioka H, Okita S, Nakano M, Minamizaki T, Nubukiyo A, Sotomaru Y, Bonnelye E, Kozai K, Tanimoto K, Aubin JE, Yoshiko Y
  • Journal Title: JBMR Plus Volume: - Issue: 6
  • DOI: 10.1002/jbm4.10496
  • NAID: 120007183697
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A bilateral third head of the gastrocnemius which is morphologically similar to the plantaris. (2021)
  • Author(s): Ishii T, Kawagishi K, Hayashi S, Yamada S, Yoshioka H, Matsuno Y, Mori Y and Kosaka J.
  • Journal Title: Surgical & Radiologic Anatomy Volume: 印刷中 Issue: 7 Pages: 1095-1098
  • DOI: 10.1007/s00276-020-02670-w
  • Peer Reviewed
• [Journal Article] Active sites of human MEPE-ASARM regulating bone matrix mineralization (2020)
  • Author(s): Minamizaki T, Sakurai K, Hayashi I, Toshishige M, Yoshioka H, Kozai K, Yoshiko Y
  • Journal Title: Molecular and Cellular Endocrinology Volume: 517 Pages: 110931-110931
  • DOI: 10.1016/j.mce.2020.110931
  • Peer Reviewed
• [Journal Article] The matrix vesicle cargo miR-125b accumulates in the bone matrix, inhibiting bone resorption in mice. (2020)
  • Author(s): Minamizaki T, Nakao Y, Irie Y, Ahmed F, Itoh S, Sarmin N, Yoshioka H, Nobukiyo A, Fujimoto C, Niida S, Sotomaru Y, Tanimoto K, Kozai K, Sugiyama T, Bonnelye E, Takei Y, Yoshiko Y
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 30-30
  • DOI: 10.1038/s42003-020-0754-2
  • NAID: 120006824053
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Soluble Klotho causes hypomineralization in Klotho-deficient mice (2018)
  • Author(s): Minamizaki T, Konishi Y, Sakurai K, Yoshioka H, Aubin JE, Kozai K, Yoshiko Y
  • Journal Title: Journal of Endocrinology Volume: 237 Issue: 3 Pages: 285-300
  • DOI: 10.1530/joe-17-0683
  • NAID: 120006826841
  • Peer Reviewed
• [Presentation] Early Life Stressと加齢がマウス成熟精子細胞数におよぼす影響の評価 (2022)
  • Author(s): 宮宗秀伸，高野海哉，永堀健太，李忠連，吉岡広陽，松野義晴，倉升三幸，呉曦，小川夕輝，伊藤正裕
  • Organizer: 第127回 日本解剖学総会・学術集会
• [Presentation] 献体による解剖見学実習と座学講義の組み合わせ順序による学修効果についての調査 (2022)
  • Author(s): 山口将希，牧原由紀子，竹内真太，青木章乃，田村暁大，石井貴弥，山田晋之介，吉岡広陽，松野義晴，川岸久太郎
  • Organizer: 第123回 理学療法科学学会・学術大会
• [Presentation] A synthetic peptide derived from the SIBLING protein MEPE inhibits ectopic mineralization but not bone formation. (2019)
  • Author(s): Minamizaki T, Toshishige M, Yoshioka H, Ahmed F, Mine Y, Yoshiko Y
  • Organizer: World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases
  • Int'l Joint Research
• [Presentation] Plasticity of osteoblasts and their adipogenic potential dissected by single cell RNA-sequencing. (2019)
  • Author(s): Yoshioka H, Nakano M, Minamizaki T, Kozai K, Yoshiko Y
  • Organizer: The American Society of Bone and Mineral Research 2019 Annual Meeting
  • Int'l Joint Research
• [Presentation] シングルセル解析から見た骨芽細胞の多様性と脂肪細胞分化転換能 (2019)
  • Author(s): 中野将志，吉岡広陽，南崎朋子，香西克之，吉子裕二
  • Organizer: 第124回日本解剖学会総会・全国学術集会
• [Presentation] Single-cell RNA-sequencing shows the adipogenic potential in osteoblasts. (2017)
  • Author(s): Okita S, Yoshioka H, Minamizaki T, Tanimoto K, Yoshiko Y
  • Organizer: 2017 ANZBMS-IFMRS Joint Meeting
  • Int'l Joint Research
• [Presentation] シングルセルRNA-seqによる骨芽細胞の多様性と脂肪細胞分化能の解析 (2017)
  • Author(s): 沖田紗季，吉岡広陽，南崎朋子，吉子裕二
  • Organizer: 第35回日本骨代謝学会学術集会
• [Presentation] Single-cell RNA sequencing provides molecular dissection of osteoblasts and their adipogenic potential. (2017)
  • Author(s): Nakano M, Yoshioka H, Okita S, Tanimoto K, Kozai K, Minamizaki T, Yoshiko Y
  • Organizer: 2017 Annual meeting of the American Society for Bone and Mineral Research.
  • Int'l Joint Research