TWIST1-Mediated Induction of AEBP1 in Fibroblast-Like Synoviocytes Activates Transforming Growth Factor β Signaling to Drive Angiogenesis and Promote Rheumatoid Arthritis

IF 9.9 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2026-09-28 Epub Date: 2026-04-10 DOI:10.1002/art.70124

Zhenyu Li MD, Minglong Cai MD, Wei Huang MD, Xi Wen MM, Yujing Li MD, Jun Sun PhD, Chen Zhu MD, Chao Yang PhD, Zhu Chen MD

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引用次数: 0

Abstract

Objective

Aggressive fibroblast-like synoviocytes (FLS) drive synovial hyperplasia, extracellular matrix (ECM) remodeling, and pannus formation in rheumatoid arthritis (RA). However, the pathogenic FLS subpopulations and their upstream regulators remain incompletely defined. This study aimed to (i) identify FLS subpopulation(s) responsible for synovial hyperplasia, ECM remodeling, and pannus development, (ii) elucidate the molecular mechanisms regulating their pathogenic activation, and (iii) explore therapeutic strategies targeting FLS activation and pannus-associated neovascularization in RA.

Methods

We integrated bulk RNA sequencing, proteomics, and single-cell transcriptomics to identify pathogenic FLS subpopulation(s) in RA synovium. Functional assays were conducted to assess the effects of adipocyte enhancer-binding protein 1 (AEBP1) and periostin (POSTN) expression on FLS activation, ECM remodeling, and angiogenesis. Bioinformatic analyses and cell biologic experiments were adopted to identify the upstream regulator responsible for AEBP1 expression in FLS. We subsequently investigated the pathologic impact of TWIST1–AEBP1–POSTN axis in a collagen-induced arthritis (CIA) mice model.

Results

We identified a pathogenic POSTN⁺ FLS subgroup selectively enriched within the sublining layer of synovium that exhibited robust ECM remodeling and fibrogenic features. Mechanistically, we showed that AEBP1 was selectively elevated in these cells, in which it activated transforming growth factor β signaling to drive fibroblast activation, migration, and proliferation. Besides, AEBP1 also induced POSTN expression, which was responsible for neovascularization. Further, inflammatory signalings induced TWIST1 expression, which directly regulated AEBP1 transcription in FLS. Intra-articular modulation of AEBP1 in mice with CIA had opposite effects on synovial hyperplasia, bone erosion, and pannus formation. Moreover, the pharmacological inhibition of TWIST1 by harmine-reduced AEBP1 and POSTN expression, limited the expansion of pathogenic THY1⁺ FLS, and alleviated joint pathology.

Conclusion

Our study suggests that POSTN⁺ FLS located in the synovial sublining contribute to RA progression through the TWIST1–AEBP1–POSTN axis. Accordingly, targeting of this axis may offer a novel and effective approach for RA treatment.

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twist1介导的AEBP1诱导成纤维细胞样滑膜细胞激活TGF-β信号驱动血管生成并促进类风湿关节炎

目的：类风湿关节炎（RA）患者侵袭性成纤维细胞样滑膜细胞（FLS）驱动滑膜增生、细胞外基质（ECM）重塑和滑膜形成。然而，致病性FLS亚群及其上游调控因子仍未完全确定。本研究旨在(i)确定与滑膜增生、ECM重塑和输卵管发育有关的FLS亚群；（ii）阐明调节其致病激活的分子机制，（iii）探索针对RA中FLS激活和pannus相关新生血管的治疗策略。方法采用整体rna测序、蛋白质组学和单细胞转录组学方法鉴定类风湿滑膜致病性FLS亚群。通过功能分析来评估AEBP1和POSTN表达对FLS激活、ECM重塑和血管生成的影响。通过生物信息学分析和细胞生物学实验，确定了FLS中负责AEBP1表达的上游调控因子。随后，我们研究了TWIST1-AEBP1-POSTN轴对CIA小鼠模型的病理影响。结果：我们发现了一个在滑膜下层选择性富集的致病性POSTN+ FLS亚群，该亚群表现出强大的ECM重塑和纤维化特征。在机制上，我们发现AEBP1在这些细胞中选择性地升高，在那里它激活TGF-β信号传导，驱动成纤维细胞的激活、迁移和增殖。此外，AEBP1还诱导了负责新生血管形成的POSTN的表达。此外，炎症信号诱导TWIST1表达，直接调控了FLS中AEBP1的转录。CIA小鼠关节内调节AEBP1对滑膜增生、骨质侵蚀和滑膜形成有相反的作用。此外，鼠碱对TWIST1的药理抑制降低了AEBP1和POSTN的表达，限制了致病性THY1+ FLS的扩增，减轻了关节病理。结论我们的研究表明，位于滑膜下层的POSTN+ FLS通过TWIST1-AEBP1-POSTN轴参与RA的进展。因此，靶向这一轴可能为RA的治疗提供一种新的有效途径。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.