DDIT3/CHOP mediates the inhibitory effect of ER stress on chondrocyte differentiation by AMPKα-SIRT1 pathway.

Xijie Yu, Xiaoxiao Xu, Wei Dong, Chang Yang, Yao Luo, Ying He, Chenxi Jiang, Yanru Wu, Jiawei Wang

Biochimica et biophysica acta. Molecular cell research 2022 Aug

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Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response related to multiple diseases, including temporomandibular joint (TMJ) cartilage-related diseases. Recent studies have indicated that DDIT3/CHOP (a downstream transcription factor of ER stress) is an important effector in mediating ER stress to inhibit chondrogenesis. However, the underlying mechanism by which DDIT3 regulates chondrogenesis remains unclear. In this study, tunicamycin (an ER stress agonist)-induced ER stress inhibited chondrocyte differentiation and matrix synthesis in vitro and led to an osteoarthritis-like phenotype in mouse TMJ cartilage. Meanwhile, DDIT3 expression in chondrocytes was robustly upregulated. Loss-of-function experiments validated the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Mechanistically, the inhibiting effect was attributed to the direct and indirect regulatory effect of DDIT3 on SIRT1 (sirtuin1, silent mating type information regulation protein type 1, a member of NAD+ dependent class III histone deacetylases). On one hand, DDIT3 directly promoted the transcription of SIRT1. On the other hand, DDIT3 indirectly increased the expression of SIRT1 by promoting AMPKα phosphorylation and activation. Furthermore, activation of AMPKα or SIRT1 with the corresponding agonist AICAR or resveratrol in the DDIT3-knockdown cells partially restored the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Collectively, these novel findings indicate that DDIT3 regulates the inhibitory effect of ER stress on chondrocyte differentiation and matrix synthesis partially via the AMPKα-SIRT1 pathway. A thorough understanding of ER stress in regulating chondrocyte homeostasis and its role in the onset of osteoarthritis may be promising to develop therapeutic targets and prevent condyle cartilage destruction. Copyright © 2022 Elsevier B.V. All rights reserved.

Citation

Xijie Yu, Xiaoxiao Xu, Wei Dong, Chang Yang, Yao Luo, Ying He, Chenxi Jiang, Yanru Wu, Jiawei Wang. DDIT3/CHOP mediates the inhibitory effect of ER stress on chondrocyte differentiation by AMPKα-SIRT1 pathway. Biochimica et biophysica acta. Molecular cell research. 2022 Aug;1869(8):119265