Zhou Haikang, Li Guoqing, Wang Yang, Jiang Rendong, Li Yicheng, Wang Huhu, Wang Fei, Ma Hairong, Cao Li
Department of Orthopaedics, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Xinjiang Uygur Autonomous Region Clinical Research Center for Orthopedic Diseases, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Front Pharmacol. 2021 Apr 9;12:659597. doi: 10.3389/fphar.2021.659597. eCollection 2021.
Osteoarthritis (OA) is a degenerative joint disease with multiple etiologies that affects individuals worldwide. No effective interventions are currently available to reverse the pathological process of OA. Sodium butyrate (NaB), a component of short-chain fatty acids (SCFAs), has multiple biological activities, including the attenuation of inflammation and anti-tumor activities in various diseases. However, whether the protective effects of NaB in OA are associated with the promotion of autophagy had not been investigated. Here, we explored the chondroprotective properties of NaB in an interleukin (IL)-1β-induced inflammatory chondrocyte model and an anterior cruciate ligament transection (ACLT) mouse model. Hematoxylin and eosin (HE), Safranin O, and immunohistochemical staining were performed to evaluate the effects of NaB treatment on articular cartilage. An optimal NaB dose for chondrocyte treatment was determined cell counting kit-8 assays. Immunofluorescence and transmission electron microscopy were used to detect autophagy in chondrocytes. Flow cytometry was utilized to detect reactive oxygen species (ROS), cell cycle activity, and apoptosis in chondrocytes. Western blot and immunostaining were performed to evaluate the protein expression levels of relevant indicators. We found that the administration of NaB by oral gavage could attenuate cartilage degradation. In parallel, NaB treatment could enhance the activation of autophagy, increase autophagic flux, decrease extracellular matrix degradation, and reduce apoptosis by restraining inflammation, ROS production, and cell cycle arrest in IL-1β-treated chondrocytes. The protective effects of NaB could be partially abolished by the autophagy inhibitor 3-methyladenine (3-MA), which indicated that the protective effects of NaB against OA were partially governed by the enhancement of autophagy to restrain the formation of inflammatory mediators and ROS and regulate cell cycle progression and apoptosis in chondrocytes. In conclusion, NaB could attenuate OA progression by restoring impaired autophagy and autophagic flux the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway, both and , implying that NaB could represent a novel therapeutic approach for OA.
骨关节炎（OA）是一种病因多样的退行性关节疾病，影响着全球各地的人群。目前尚无有效的干预措施来逆转OA的病理过程。丁酸钠（NaB）是短链脂肪酸（SCFAs）的一种成分，具有多种生物学活性，包括减轻炎症以及在各种疾病中的抗肿瘤活性。然而，NaB在OA中的保护作用是否与自噬的促进有关尚未得到研究。在此，我们在白细胞介素（IL）-1β诱导的炎性软骨细胞模型和前交叉韧带横断（ACLT）小鼠模型中探究了NaB的软骨保护特性。进行苏木精和伊红（HE）染色、番红O染色以及免疫组织化学染色以评估NaB处理对关节软骨的影响。通过细胞计数试剂盒-8检测确定了软骨细胞处理的最佳NaB剂量。利用免疫荧光和透射电子显微镜检测软骨细胞中的自噬。采用流式细胞术检测软骨细胞中的活性氧（ROS）、细胞周期活性和细胞凋亡。进行蛋白质印迹和免疫染色以评估相关指标的蛋白质表达水平。我们发现通过灌胃给予NaB可减轻软骨降解。同时，NaB处理可增强自噬的激活，增加自噬通量，减少细胞外基质降解，并通过抑制IL-1β处理的软骨细胞中的炎症、ROS产生和细胞周期停滞来减少细胞凋亡。自噬抑制剂3-甲基腺嘌呤（3-MA）可部分消除NaB的保护作用，这表明NaB对OA的保护作用部分是通过增强自噬来抑制炎性介质和ROS的形成，并调节软骨细胞的细胞周期进程和细胞凋亡。总之，NaB可通过恢复受损的自噬和自噬通量以及磷酸肌醇3-激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素哺乳动物靶蛋白（mTOR）通路来减轻OA进展，这意味着NaB可能代表一种治疗OA的新方法。
