PU.1 regulates osteoarthritis progression via CSF1R in synovial cells

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2024-09-21 DOI:10.1016/j.bbadis.2024.167525

Tingting Wang , Jiakai Wang , Tao Sun , Rong Zhang , Yishuo Li , Tianyu Hu

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引用次数: 0

Abstract

This study elucidates the molecular mechanisms driving osteoarthritis (OA) by focusing on the transcription factor PU.1's role in synovial cells, specifically macrophages and fibroblast-like synoviocytes (FLS). Analyzing OA-related synovial gene expression from the GEO database highlighted immune regulation pathways in OA. Using protein-protein interaction and the JASPAR database, we pinpointed essential genes in OA development. Synovial tissues from OA patients and controls revealed pronounced PU.1 and its target CSF1R presence. In a surgically induced OA mouse model with PU.1 and CSF1R knockdown, ChIP assays confirmed PU.1's binding to the CSF1R promoter. Dual luciferase reporter assays and immunohistochemistry validated PU.1's regulatory impact on CSF1R transcription. Combined analysis of microarrays GSE55235 and GSE206848 showed heightened PU.1 expression in OA, associated with immune regulation in macrophages. In vitro findings aligned with in vivo results, emphasizing PU.1's influence on macrophage polarization and FLS-induced inflammation. PU.1's direct activation of CSF1R transcription underpins its key role in OA progression. This research offers insights into OA's molecular basis, suggesting potential therapeutic targets.

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PU.1通过滑膜细胞中的CSF1R调节骨关节炎的发展。

本研究通过重点研究转录因子 PU.1 在滑膜细胞，特别是巨噬细胞和成纤维细胞样滑膜细胞（FLS）中的作用，阐明了驱动骨关节炎（OA）的分子机制。通过分析GEO数据库中与OA相关的滑膜基因表达，突出了OA中的免疫调节通路。利用蛋白-蛋白相互作用和 JASPAR 数据库，我们确定了 OA 发育过程中的重要基因。来自 OA 患者和对照组的滑膜组织显示了明显的 PU.1 及其目标 CSF1R 的存在。在手术诱导的 OA 小鼠模型中，PU.1 和 CSF1R 被敲除，ChIP 分析证实了 PU.1 与 CSF1R 启动子的结合。双荧光素酶报告实验和免疫组化验证了 PU.1 对 CSF1R 转录的调控作用。对微阵列 GSE55235 和 GSE206848 的综合分析表明，PU.1 在 OA 中的表达增加与巨噬细胞的免疫调节有关。体外研究结果与体内研究结果一致，强调了 PU.1 对巨噬细胞极化和 FLS 诱导的炎症的影响。PU.1 对 CSF1R 转录的直接激活是其在 OA 进展中发挥关键作用的基础。这项研究深入揭示了 OA 的分子基础，并提出了潜在的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.