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.

中文翻译：

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中和血管生成素样蛋白 4 单克隆抗体在类风湿性关节炎中的骨保护作用


尽管最近取得了进展，但类风湿性关节炎 （RA） 患者仍然对治疗难治。血管生成素样蛋白 4 （ANGPTL4） 的失调过量被认为会导致疾病的发展。ANGPTL4 最初被确定为脂质代谢的调节因子，脂质代谢在 体内水解为 N 端和 C 端 （cANGPTL4） 片段。cANGPTL4 参与几个非脂质相关过程，包括血管生成和炎症。这项研究表明，与对照组相比，RA 患者血清和滑膜组织中的 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） 的动物模型中，施用抗 cANGPTL4 的中和抗体（抗 cANGPTL4 Ab）可抑制炎症过程和骨质流失。AIA 模型中滑膜组织的转录组学和蛋白质组学分析表明，抗 cANGPTL4 抗体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 抗体已被证明可通过 sirtuin 1/核因子-κB 信号通路抑制 TNF α诱导的 RA-FLS 炎症级联反应。此外，发现抗 cANGPTL4 抗体可阻断 FLS 侵袭和移民诱导的破骨细胞活化。总的来说，这些发现将 ANGPTL4 确定为诊断 RA 的前瞻性生物标志物，靶向 cANGPTL4 应该代表一种潜在的治疗策略。