Bone-protective effects of neutralizing angiopoietin-like protein 4 monoclonal antibody in rheumatoid arthritis

类风湿性关节炎 单克隆抗体 抗体 免疫学 病毒学 单克隆 医学
作者
Liqing Ke,Qifei He,Jing Qu,Xiyue Wang,Kaibo Li,Xun Gong,Lan Li,Jiake Xu,Qiuliyang Yu,Sheng Wang,Xuefei Lin,Jian Li,Nguan Soon Tan,Wei Sun,Li Liang,Peng Zhang,Wenxiang Cheng
出处
期刊:Molecular Therapy [Elsevier]
标识
DOI:10.1016/j.ymthe.2024.09.031
摘要

Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like 4 protein (ANGPTL4) is thought to be contributed to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal (nANGPTL4) and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. The present 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 (CIA) and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocytes (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 may represent a potential therapeutic strategy.
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