Xie Peng-Yu, Li Shan-Shan, Liang Xu, Ma Hang, Yang Ying-Chao, Li Tian-Fang
Department of Rheumatology, First Affiliated Hospital of Zhengzhou University, No.1 Jianshe Dong Road, Zhengzhou, 450052, China.
Mol Cell Biochem. 2025 Jul 12. doi: 10.1007/s11010-025-05349-1.
Although osteoarthritis (OA) is a leading cause of morbidity, no disease-modifying osteoarthritis drugs (DMOADs) are currently available. An in-depth understanding of OA pathogenesis may help the development of novel and effective treatments. Activating transcription factor 4 (ATF-4) plays a critical role in skeletal biology as it is closely involved in ER stress, autophagy, cell senescence, etc. Our study showed that meniscal injury in Atf-4 deficient (Atf-4) mice resulted in complete destruction of mouse knee joints. In addition, these mice developed spontaneous OA-like lesions with aging. In vitro study demonstrated that the ER stress was increased and proliferation was decreased in articular chondrocytes from Atf-4 mice compared to wild-type (WT) chondrocytes, which enhanced apoptosis of Atf-4 chondrocytes. Re-introduction of ATF-4 into the joint cavity of Atf-4 mice significantly alleviated joint damage. Taken together, our study demonstrates that ATF-4 is a critical molecule for normal functionality of articular chondrocytes and its modification may facilitate the identification of novel therapeutic targets.
尽管骨关节炎（OA）是导致发病的主要原因，但目前尚无改善病情的骨关节炎药物（DMOADs）。深入了解OA发病机制可能有助于开发新的有效治疗方法。激活转录因子4（ATF-4）在骨骼生物学中起关键作用，因为它与内质网应激、自噬、细胞衰老等密切相关。我们的研究表明，Atf-4基因缺陷（Atf-4）小鼠的半月板损伤导致小鼠膝关节完全破坏。此外，这些小鼠随着年龄增长出现自发性OA样病变。体外研究表明，与野生型（WT）软骨细胞相比，Atf-4小鼠关节软骨细胞的内质网应激增加，增殖减少，这增强了Atf-4软骨细胞的凋亡。将ATF-4重新引入Atf-4小鼠的关节腔可显著减轻关节损伤。综上所述，我们的研究表明，ATF-4是关节软骨细胞正常功能的关键分子，对其进行调控可能有助于确定新的治疗靶点。
