NR4A1 promotes TNF‑α‑induced chondrocyte death and migration injury via activating the AMPK/Drp1/mitochondrial fission pathway

Nuclear receptor subfamily 4 group A member 1 (NR4A1)induced chondrocyte death plays a critical role in the development of osteoarthritis through poorly defined mechanisms. The present study aimed to investigate the role of NR4A1 in regulating chondrocyte death in response to tumor necrosis factoralpha (TNFalpha) and cycloheximide (CHX) treatment, with a focus on mitochondrial fission and the AMPactivated protein kinase (AMPK) signaling pathway. The results demonstrated that NR4A1 was significantly upregulated in TNFalpha and CHX exposed chondrocytes. Increased NR4A1 triggered mitochondrial fission via the AMPK/dynaminrelated protein 1 (Drp1) pathway, resulting in mitochondrial dysfunction, and mitochondrial permeability transition pore (mPTP) openingrelated cell death. Furthermore, excessive mitochondrial fission impaired chondrocyte migration through imbalance of Factin homeostasis. Inhibiting NR4A1 attenuated TNFalpha and CHXinduced mitochondrial fission and, thus, reduced mitochondrial dysfunction in chondrocytes, mPTP openingrelated cell death and migration injury. Altogether, the present data confirmed that mitochondrial fission was involved in NR4A1mediated chondrocyte injury via regulation of mitochondrial dysfunction, mPTP openinginduced cell death and Factinrelated migratory inhibition.