Epigenetic analysis of regulating bone and mineral metabolism under rare disease in orthognathic lesion

2023 Fiscal Year Final Research Report

• Project/Area Number: 18KK0464
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57070:Developmental dentistry-related
• Research Institution: Okayama University (2019-2023); The University of Tokushima (2018)
• Principal Investigator: Izawa Takashi 岡山大学, 医歯薬学域, 准教授 (30380017)
• Project Period (FY): 2019 – 2023
• Keywords: 破骨細胞 / エピゲノム / RANKL / 顎顔面領域稀少性遺伝子疾患 / 骨細胞

Outline of Final Research Achievements

Both LRF and ThPOK belong to the POK family of transcription repressors. Although LRF mediates osteoclast differentiation by regulating NFATc1 expression, the principal established function of ThPOK is transcriptional control of T-cell lineage commitment. Whether ThPOK affects osteoclast formation is not known. We find that marrow macrophage ThPOK expression diminishes with exposure to RANKL, but ThPOK deficiency does not affect osteoclast differentiation. On the other hand, enhanced ThPOK,in macrophages, substantially impairs osteoclastogenesis. Excess ThPOK binds the NFATc1 promoter and suppresses its transcription, suggesting a mechanism for its osteoclast inhibitory effect. Despite suppression of osteoclastogenesis by excess ThPOK being associated with diminished NFATc1, osteoclast formation is not rescued by NFATc1 overexpression. Thus, ThPOK appears to inhibit NFATc1 transcription and its osteoclastogenic capacity, while its depletion has no effect on the bone-resorptive cell.

Free Research Field

歯科矯正学

Academic Significance and Societal Importance of the Research Achievements

最近、我々は破骨細胞活性化因子のRANKLとダイオキシン受容体AhRとのシグナルクロストーク解明によるマクロファージから破骨細胞への分化機構の一端を明らかにした。ダイオキシン受容体の遺伝子破壊により、リガンド暴露による口蓋裂がなくなるという報告もあり、生物作用への直接的な関与が示されはじめている。また、歯科用レジンにも含まれるAhRリガンドが内分泌撹乱物質として働き破骨細胞分化を著しく抑制するといった報告もあり、免疫細胞内でのAhRシグナル伝達機構や病的状況下での動態解析がダイオキシンの毒性発現、骨量調節のメカニズム解明に本質的な知見を与えると共に、歯学系領域からの情報発信につながると考える。