Erbacher Christoph, Vaknine-Treidel Shani, Madrer Nimrod, Weinbender Sofia, Evdokimov Dimitar, Unterecker Stefan, Moshitzky Gilli, Sommer Claudia, Greenberg David S, Soreq Hermona, Üçeyler Nurcan
Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Pain. 2024 Dec 6;166(7):1641-1652. doi: 10.1097/j.pain.0000000000003499.
Fibromyalgia syndrome (FMS) is a debilitating widespread chronic pain condition of unclear pathophysiology. We studied small noncoding RNAs as potential classifiers and mediators of FMS. Blood and keratinocyte microRNAs (miRs) and transfer RNA fragments (tRFs) were profiled by small RNA-sequencing within a comprehensively phenotyped female cohort of 53 patients with FMS vs 34 healthy controls (hCOs) and 15 patients with major depression and chronic physical pain (disease controls). Small RNAs were quantified via RNA-sequencing and candidates validated via qRT-PCR. MicroRNAs and tRFs were tested for association with FMS symptoms and their potential regulatory roles. miR and tRF profiles were altered in FMS compared to hCO in whole blood (n = 69; n = 22) and keratinocytes (n = 41; n = 55). Receiver operating characteristic analysis of blood miR candidates hsa-miR-148a-3p and hsa-miR-182-5p, and tRF candidate tRF-21-WB8647O5D levels separated FMS from hCO. In blood, hsa-miR-182-5p and hsa-miR-576-5p upregulation was validated via qRT-PCR, showing even higher expression in disease control, while TRF-20-40KK5Y93 was selectively increased in FMS. MicroRNAs in blood and keratinocytes were associated with how widespread pain manifested in patients. Keratinocyte tRFs correlated with loss of skin innervation. In blood, altered small RNAs were linked to immune and RNA processes, whereas in keratinocytes, adhesion and epithelial functions were targeted. Modulated tRFs shared sequence motifs in patients with FMS, which may promote concerted pathway regulation. Our findings show miRs/tRFs as key small RNAs dysregulation in FMS pathophysiology and open new perspectives for FMS diagnostics, symptom monitoring, and clinical management.
纤维肌痛综合征（FMS）是一种病因不明、使人衰弱的广泛性慢性疼痛病症。我们研究了小非编码RNA作为FMS的潜在分类标志物和介质。通过小RNA测序对53例FMS女性患者、34例健康对照（hCO）以及15例伴有重度抑郁和慢性身体疼痛的患者（疾病对照）这一全面表型化的队列中的血液和角质形成细胞微小RNA（miR）及转运RNA片段（tRF）进行分析。通过RNA测序对小RNA进行定量，并通过qRT-PCR对候选物进行验证。测试微小RNA和tRF与FMS症状的相关性及其潜在调节作用。与hCO相比，FMS患者全血（n = 69；n = 22）和角质形成细胞（n = 41；n = 55）中的miR和tRF谱发生了改变。对血液miR候选物hsa-miR-148a-3p和hsa-miR-182-5p以及tRF候选物tRF-21-WB8647O5D水平进行的受试者工作特征分析将FMS与hCO区分开来。在血液中，通过qRT-PCR验证了hsa-miR-182-5p和hsa-miR-576-5p的上调，其在疾病对照中的表达更高，而TRF-20-40KK5Y93在FMS中选择性增加。血液和角质形成细胞中的微小RNA与患者广泛性疼痛的表现方式相关。角质形成细胞tRF与皮肤神经支配丧失相关。在血液中，改变的小RNA与免疫和RNA过程相关，而在角质形成细胞中，黏附和上皮功能是靶点。FMS患者中受调节的tRF具有共同的序列基序，这可能促进协同的信号通路调节。我们的研究结果表明，miR/tRF是FMS病理生理学中关键的小RNA失调，为FMS的诊断、症状监测和临床管理开辟了新的前景。
