Ke Liqing, He Qifei, Qu Jing, Wang Xiyue, Li Kaibo, Gong Xun, Li Lan, Xu Jiake, Yu Qiuliyang, Yu Hao, Lin Xuefei, Li Jian, Tan Nguan Soon, Sun Wei, Li Liang, Zhang Peng, Cheng Wenxiang
Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
Department of Bone Joint and Musculoskeletal Tumor, Shenzhen Second People's Hospital (The First Affiliated Hospital of Shenzhen University), Shenzhen, Guangdong 518035, China.
Mol Ther. 2024 Dec 4;32(12):4497-4513. doi: 10.1016/j.ymthe.2024.09.031. Epub 2024 Oct 4.
Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like protein 4 (ANGPTL4) is thought to contribute to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. This study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from an AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 should represent a potential therapeutic strategy.
尽管最近取得了进展，但类风湿性关节炎（RA）患者对治疗仍具有抗性。血管生成素样蛋白4（ANGPTL4）的过量产生失调被认为与疾病发展有关。ANGPTL4最初被鉴定为脂质代谢的调节因子，在体内可水解为N端和C端（cANGPTL4）片段。cANGPTL4参与多种非脂质相关过程，包括血管生成和炎症。本研究表明，与对照组相比，RA患者血清和滑膜组织中ANGPTL4水平显著升高。在胶原诱导的关节炎和佐剂诱导的关节炎（AIA）动物模型中，给予抗cANGPTL4中和抗体（抗cANGPTL4 Ab）可抑制炎症过程和骨质流失。对AIA模型滑膜组织的转录组和蛋白质组分析表明，抗cANGPTL4 Ab可抑制成纤维细胞样滑膜细胞（FLS）迁移和炎症诱导的破骨细胞生成。从机制上讲，抗cANGPTL4 Ab已被证明可通过沉默调节蛋白1/核因子-κB信号通路抑制RA-FLS中肿瘤坏死因子-α诱导的炎症级联反应。此外，发现抗cANGPTL4 Ab可阻断FLS侵袭和迁移诱导的破骨细胞激活。总的来说，这些发现确定ANGPTL4为RA诊断的潜在生物标志物，靶向cANGPTL4应是一种潜在的治疗策略。
