17β-雌二醇通过调节 FTO/IGF2BP1/m6A-NLRC5 轴促进颞下颌关节骨关节炎的进展。
17β-estradiol promotes the progression of temporomandibular joint osteoarthritis by regulating the FTO/IGF2BP1/m6A-NLRC5 axis.
机构信息
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China.
出版信息
Immun Inflamm Dis. 2024 Aug;12(8):e1361. doi: 10.1002/iid3.1361.
BACKGROUND
Temporomandibular joint osteoarthritis (TMJOA) is a degenerative cartilage disease. 17β-estradiol (E2) aggravates the pathological process of TMJOA; however, the mechanisms of its action have not been elucidated. Thus, we investigate the influence of E2 on the cellular biological behaviors of synoviocytes and the molecular mechanisms.
METHODS
Primary fibroblast-like synoviocytes (FLSs) isolated from rats were treated with TNF-α to establish cell model, and phenotypes were evaluated using cell counting kit-8, EdU, Tanswell, enzyme-linked immunosorbent assay, and quantitative real-time PCR (qPCR). The underlying mechanism of E2, FTO-mediated NLRC5 m6A methylation, was assessed using microarray, methylated RNA immunoprecipitation, qPCR, and western blot. Moreover, TMJOA-like rat model was established by intra-articular injection of monosodium iodoacetate (MIA), and bone morphology and pathology were assessed using micro-CT and H&E staining.
RESULTS
The results illustrated that E2 facilitated the proliferation, migration, invasion, and inflammation of TNF-α-treated FLSs. FTO expression was downregulated in TMJOA and was reduced by E2 in FLSs. Knockdown of FTO promoted m6A methylation of NLRC5 and enhanced NLRC5 stability by IGF2BP1 recognition. Moreover, E2 promoted TMJ pathology and condyle remodeling, and increased bone mineral density and trabecular bone volume fraction, which was rescued by NLRC5 knockdown.
CONCLUSION
E2 promoted the progression of TMJOA.
背景
颞下颌关节骨关节炎（TMJOA）是一种退行性软骨疾病。17β-雌二醇（E2）加重 TMJOA 的病理过程；然而，其作用机制尚未阐明。因此，我们研究了 E2 对滑膜细胞的细胞生物学行为及其分子机制的影响。
方法
用 TNF-α处理原代纤维样滑膜细胞（FLS）建立细胞模型，用细胞计数试剂盒-8、EdU、Tanswell、酶联免疫吸附测定和实时定量 PCR（qPCR）评估表型。用微阵列、甲基化 RNA 免疫沉淀、qPCR 和 Western blot 评估 E2、FTO 介导的 NLRC5 m6A 甲基化的潜在机制。此外，通过关节内注射单碘乙酸盐（MIA）建立 TMJOA 样大鼠模型，用 micro-CT 和 H&E 染色评估骨形态和病理学。
结果
结果表明，E2 促进了 TNF-α 处理的 FLSs 的增殖、迁移、侵袭和炎症。FTO 在 TMJOA 中表达下调，在 FLSs 中被 E2 下调。FTO 敲低促进了 NLRC5 的 m6A 甲基化，并通过 IGF2BP1 识别增强了 NLRC5 的稳定性。此外，E2 促进了 TMJ 病理学和髁突重塑，增加了骨矿物质密度和小梁骨体积分数，NLRC5 敲低可挽救这些改变。
结论
E2 促进了 TMJOA 的进展。
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