Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis

类风湿性关节炎 成纤维细胞 医学 感觉神经 感觉系统 神经生长因子 病理 基因表达 成纤维细胞生长因子 滑膜 基因 免疫学 生物 神经科学 受体 内科学 遗传学 体外
作者
Zilong Bai,Nicholas Bartelo,Maryam Aslam,Elisabeth A. Murphy,Caryn Hale,Nathalie E. Blachère,Salina Parveen,Edoardo Spolaore,Edward F. DiCarlo,Ellen M. Gravallese,Melanie H. Smith,Mayu O. Frank,Caroline S. Jiang,Haotan Zhang,Christina Pyrgaki,Myles Lewis,Shafaq Sikandar,Costantino Pitzalis,Joseph B. Lesnak,Khadijah Mazhar
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science]
卷期号:16 (742) 被引量:22
标识
DOI:10.1126/scitranslmed.adk3506
摘要

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene–related peptide (CGRP + ). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP + dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP + pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.
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