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関節軟骨最表層におけるWnt/Ctnnb1シグナルの機能解析

玄, 峰俊 東京大学 DOI:10.15083/0002006243

2023.03.24

概要

[課程-2]
審査の結果の要旨
氏名 玄

峰俊

本研究では、Wnt /Ctnnb1 シグナルが成体関節軟骨の SFZ において重要な役割を果たす
ことを以下の3つの結果から実証した。
1.

Wnt /Ctnnb1 シグナルは成体関節軟骨の SFZ のみで活性化され、Prg4 陽性細胞におけ
る機能喪失は SFZ の変性を伴う OA の進行につながり、一方、機能獲得は OA による
軟骨変性に対する耐性を示す。

2.

Prg4 の発現は Wnt /Ctnnb1 シグナルにより誘導され、力学的負荷は SFZ 細胞における
Wnt リガンドおよび Prg4 の発現を増加させる。

3.

Wnt /Ctnnb1 シグナル伝達は Prg4 の代表的な転写因子である Creb1 を誘導し、Prg4 の
発現を誘導する。Wnt /Ctnnb1 シグナルは骨格発達における SFZ の特徴付けと形成に
寄与し、成人関節軟骨の維持にも必要であることをこれらの結果よりで示唆した。
以上、Wnt/Ctnnb1 シグナルは成体関節軟骨の SFZ で活性化しており、そのメカニズムと

して力学的負荷が SFZ における Wnt ligand の発現を維持している一方で、Creb1 の誘導を
介して Prg4 の発現を誘導し、関節を保護していることを実証した。本研究で得られた知見
から関節軟骨最表層に発現する Prg4 は Wnt シグナルにより発現上昇し、Wnt シグナルの
アゴニストまたはリガンドは関節軟骨最表層を保護する変形性膝関節症治療候補薬になる
可能性が示唆された。
よって本論文は博士(医学)の学位請求論文として合格と認められる。

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