Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China.
Medical Research Center/Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, Shenyang, China.
Aging Cell. 2021 Feb;20(2):e13306. doi: 10.1111/acel.13306. Epub 2021 Jan 15.
Osteoarthritis (OA) is a heterogeneous disease that is extremely hard to cure owing to its complex regulation network of pathogenesis, especially cartilage degeneration. FBXO21 is a subunit of ubiquitin E3 ligases that degrades P-glycoprotein and EID1 by ubiquitination and activates the JNK and p38 pathways; however, its role in OA remains unknown. Here, the main objective of this study was to evaluate the potential effects and mechanism of FBXO21 in OA degeneration, we revealed that FBXO21 is upregulated in the cartilage of patients with OA, aging, and monosodium iodoacetate-induced OA rats, and chondrocytes treated with interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide. Moreover, the in vivo and in vitro knockdown of FBXO21 suppressed OA-related cartilage degeneration, as evidenced by activated autophagy, upregulated anabolism, alleviated apoptosis, and downregulated catabolism. In contrast, its overexpression promoted OA-related cartilage degeneration. In addition, using mass spectrometry and co-immunoprecipitation assay, we demonstrated that the downstream mechanism of FBXO21 inhibits autophagy by interacting with and phosphorylating ERK. Furthermore, FBXO21 alleviated anabolism and enhanced apoptosis and catabolism by inhibiting autophagy in rat chondrocytes. Interestingly, for its upstream mechanism, JUNB promoted FBXO21 expression by directly targeting the FBXO21 promoter, thus further accelerating cartilage degeneration in SW1353 cells and rat chondrocytes. Overall, our findings reveal that the JUNB-FBXO21-ERK axis regulates OA apoptosis and cartilage matrix metabolism by inhibiting autophagy. Therefore, FBXO21 is an attractive target for regulating OA pathogenesis, and its knockdown may provide a novel targeted therapy for OA.
骨关节炎（OA）是一种异质性疾病，由于其发病机制的复杂调控网络，尤其是软骨退变，极难治愈。FBXO21 是泛素 E3 连接酶的一个亚基，通过泛素化降解 P-糖蛋白和 EID1，并激活 JNK 和 p38 通路；然而，其在 OA 中的作用尚不清楚。本研究的主要目的是评估 FBXO21 在 OA 退变中的潜在作用和机制，我们发现 FBXO21 在 OA 患者、衰老和碘乙酸钠诱导的 OA 大鼠的软骨以及白细胞介素-1β、肿瘤坏死因子-α和脂多糖处理的软骨细胞中上调。此外，FBXO21 的体内和体外敲低抑制了 OA 相关的软骨退变，表现为自噬激活、合成代谢上调、凋亡减轻和分解代谢下调。相反，其过表达促进了 OA 相关的软骨退变。此外，通过质谱和免疫共沉淀实验，我们证明了 FBXO21 的下游机制通过与 ERK 相互作用和磷酸化来抑制自噬。此外，FBXO21 通过抑制自噬在大鼠软骨细胞中减轻合成代谢并增强凋亡和分解代谢。有趣的是，对于其上游机制，JUNB 通过直接靶向 FBXO21 启动子促进 FBXO21 的表达，从而进一步加速 SW1353 细胞和大鼠软骨细胞中的软骨退变。总之，我们的研究结果表明，JUNB-FBXO21-ERK 轴通过抑制自噬调节 OA 凋亡和软骨基质代谢。因此，FBXO21 是调节 OA 发病机制的一个有吸引力的靶点，其敲低可能为 OA 提供一种新的靶向治疗方法。
