Elucidation of the molecular mechanism of the protection of cartilage degeneration via chondrocyte death and investigation of cartilage protection by its inhibition

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09408
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Kyoto University
• Principal Investigator: Nishitani Kohei 京都大学, 医学研究科, 特定助教 (70782407)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 変形性関節症 / 軟骨損傷 / 小胞体ストレス / 炎症性サイトカイン / 力学的ストレス / MAPキナーゼ

Outline of Final Research Achievements

A novel rat model of cartilage injury was created using the cyclic compression model, in which repetitive stress is applied between the femur and tibia. The model was confirmed to be a model of traumatic cartilage injury leading to osteoarthritis. The administration of KUS121, a novel compound with a cell death inhibitory effect showed chondroprotective effects. As the mechanism of the chondroprotective effect, the inhibition of chondrocyte death was confirmed by the reduction of the endoplasmic-reticulum stress. As the mechanism of chondrocyte death inhibition, inhibition of MAP-kinase cascade and proteolytic enzymes through reduction of endoplasmic-reticulum stress response was observed.

Free Research Field

整形外科学

Academic Significance and Societal Importance of the Research Achievements

変形性関節症は対症療法と、末期での人工膝関節置換術以外に根本的な治療法がない疾患であるが、今回効果が確認されたKUS化合物による小胞体ストレス抑制による軟骨細胞死抑制効果と、それに伴う蛋白分解酵素抑制効果は、変形性関節症における軟骨保護作用を持つ可能性がある。特に外傷性の関節症では、この化合物を受傷早期に投与することにより、将来起こると考えられる軟骨損傷とその後の変形性関節症への進展を防ぐ効果が期待される。軟骨損傷と変形性関節症に対する新たな治療法となる可能性が示唆されたと考える。