Analysis on the regulatory mechanism of bone remodeling based on cellular senescence in osteocytes

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19553
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Ikebuchi Yuki 東京大学, 医学部附属病院, 助教 (20645725)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 骨代謝 / 細胞老化 / 細胞外膜小胞 / 酸化ストレス

Outline of Final Research Achievements

To examine the possibility that the accumulation of oxidative stress is involved in the acceleration of cellular senescence in osteocytes, transgenic mice, which expressing SOD1 under the osteocyte-selective Sost promoter, was generated. In addition, osteocyte-selective removal of senescent cells was attempted. Although no changes in various bone metabolism parameters were observed in young mice, we are planning to analyze the results in adult and old mice.
Analysis of mouse osteocyte-like IDG-SW3 and MLO-Y4 cells showed that oxidative stress induced by high oxygen concentration or H2O2 loading caused changes in several markers suggestive of cellular senescence. Membrane vesicles containing RANKL were secreted in the culture supernatant, suggesting that they have osteoclastogenesis ability.

Free Research Field

骨代謝

Academic Significance and Societal Importance of the Research Achievements

骨代謝回転の起点となる破骨細胞形成が、時間的・空間的にどの様に制御されているのかは未解明な点が多い。本研究から、酸化ストレスによる骨細胞の細胞老化誘導が、SASP因子の一つとしてRANKLを搭載した細胞外膜小胞を分泌し、これが破骨細胞の形成を制御している可能性が示唆された。搭載分子等のより詳細な解析に基づき、将来的に、それらを標的とした抗体分子の投与によって骨代謝回転の制御が可能になることを期待している。一連の解析により、骨リモデリングの起点となる破骨細胞形成が時間的、また空間的にどのような制御を受けているのかに関して、重要な知見を得ることが可能と考えている。