{"title":"中和血管生成素样蛋白 4 单克隆抗体对类风湿性关节炎患者骨骼的保护作用。","authors":"Liqing Ke, Qifei He, Jing Qu, Xiyue Wang, Kaibo Li, Xun Gong, Lan Li, Jiake Xu, Qiuliyang Yu, Hao Yu, Xuefei Lin, Jian Li, Nguan Soon Tan, Wei Sun, Liang Li, Peng Zhang, Wenxiang Cheng","doi":"10.1016/j.ymthe.2024.09.031","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4497-4513"},"PeriodicalIF":12.1000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638830/pdf/","citationCount":"0","resultStr":"{\"title\":\"Bone-protective effects of neutralizing angiopoietin-like protein 4 monoclonal antibody in rheumatoid arthritis.\",\"authors\":\"Liqing Ke, Qifei He, Jing Qu, Xiyue Wang, Kaibo Li, Xun Gong, Lan Li, Jiake Xu, Qiuliyang Yu, Hao Yu, Xuefei Lin, Jian Li, Nguan Soon Tan, Wei Sun, Liang Li, Peng Zhang, Wenxiang Cheng\",\"doi\":\"10.1016/j.ymthe.2024.09.031\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":19020,\"journal\":{\"name\":\"Molecular Therapy\",\"volume\":\" \",\"pages\":\"4497-4513\"},\"PeriodicalIF\":12.1000,\"publicationDate\":\"2024-12-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638830/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ymthe.2024.09.031\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/4 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.09.031","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
尽管最近取得了一些进展,但类风湿性关节炎(RA)患者对治疗仍有耐药性。血管生成素样 4 蛋白(ANGPTL4)的过度生成失调被认为是导致疾病发展的原因之一。ANGPTL4 最初被认为是脂质代谢的调节因子,在体内会水解为 N 端(nANGPTL4)和 C 端(cANGPTL4)片段。cANGPTL4 参与多个与脂质无关的过程,包括血管生成和炎症。本研究发现,与对照组相比,RA 患者血清和滑膜组织中的 ANGPTL4 水平明显升高。在胶原诱导的关节炎(CIA)和佐剂诱导的关节炎(AIA)动物模型中,服用抗 cANGPTL4 的中和抗体(抗 cANGPTL4 Ab)可抑制炎症过程和骨质流失。AIA 模型滑膜组织的转录组和蛋白质组分析表明,抗ANGPTL4 Ab 可抑制成纤维细胞样滑膜细胞(FLS)的迁移和炎症诱导的破骨细胞生成。从机理上讲,抗-CANGPTL4抗体可通过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,研究还发现抗 ANGPTL4 Ab 可阻断 FLS 入侵和移民诱导的破骨细胞活化。总之,这些研究发现ANGPTL4是诊断RA的一种前瞻性生物标记物,以cANGPTL4为靶点可能是一种潜在的治疗策略。
Bone-protective effects of neutralizing angiopoietin-like protein 4 monoclonal antibody in rheumatoid arthritis.
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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.