Mapping and Analysis of Protein and Gene Profile Identification of the Important Role of Transforming Growth Factor Beta in Synovial Invasion in Patients With Pigmented Villonodular Synovitis

IF 11.4 1区医学 Q1 RHEUMATOLOGY Arthritis & Rheumatology Pub Date : 2024-07-08 DOI:10.1002/art.42946

Tao Li, Yan Xiong, Jian Li, Xin Tang, Yutong Zhong, Zhigang Tang, Qiuping Zhang, Yubin Luo

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Abstract

Objective

Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft-tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved.

Methods

The expression of synovial genes from 6 control individuals, 7 patients with osteoarthritis (OA), and 19 patients with PVNS was analyzed via RNA sequencing. Protein profiles from 5 control individuals, 10 patients with OA, and 32 patients with PVNS were analyzed using label-free proteomics. Microarray and reverse transcription–polymerase chain reaction analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from tissue of patients with PVNS. Various signaling pathway inhibitors, small interfering RNAs, and Western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed.

Results

In total, 522 differentially expressed proteins were identified in the tissues of patients with PVNS. By integrating RNA sequencing and microarray analyses, significant changes in the expression of epithelial–mesenchymal transition (EMT)-related genes, including transforming growth factor TGF-b induced, neural cadherin, epithelial cadherin, SNAIL, and TWIST, were confirmed in the tissue of patients with PVNS compared to the control tissue. In vitro, TGFβ induced EMT and increased epithelial cell migration and invasion. Moreover, TGFβ not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways.

Conclusion

This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGFβ in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy.

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蛋白质和基因图谱的绘制与分析确定了 TGF-β 在色素性绒毛膜滑膜炎滑膜侵袭中的重要作用。

背景：色素性绒毛结节性滑膜炎（PVNS）是一种罕见的良性增生性疾病，会影响滑膜关节和肌腱内的软组织。人们对其病因知之甚少，这在很大程度上限制了现有治疗方案的可用性。在此，我们绘制了 PVNS 患者滑膜基因和蛋白质图谱，揭示了滑膜炎症和侵袭之间的联系，并阐明了其中潜在的分子机制：方法：通过 RNA 测序分析了 6 名对照组患者、7 名 OA 患者和 19 名 PVNS 患者的滑膜基因表达。使用无标记蛋白质组学分析了五名对照组患者、十名 OA 患者和三十二名 PVNS 患者的蛋白质谱。微阵列、RT-PCR 分析和免疫组化染色用于评估滑膜组织、上皮细胞和来自 PVNS 组织的滑膜成纤维细胞（FLSs）中炎性细胞因子和靶基因的表达水平。各种信号通路抑制剂、siRNA 和 Western 印迹被用于分子机制研究。随后进行了Transwell迁移和侵袭试验：结果：在 PVNS 组织中总共发现了 522 个差异表达蛋白。通过整合 RNA 测序和芯片分析，证实与对照组织相比，PVNS 组织中 EMT 相关基因的表达发生了显著变化，包括 TGFBI、N-cadherin、E-cadherin、SNAIL 和 TWIST。在体外，TGF-β 可诱导 EMT 并增加上皮细胞的迁移和侵袭。此外，TGF-β不仅促进了上皮细胞与FLS之间的相互作用，还通过激活经典的Smad2/3和非经典的JNK/AKT信号通路，直接提高了FLS的迁移和侵袭能力：本研究提供了PVNS的整体蛋白和基因图谱，并确定了TGF-β在滑膜侵袭病理学中的关键作用。探索相关的分子机制也可能为 PVNS 的治疗提供新的策略或靶点。

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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.