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

作者：Zilong Bai, Nicholas Bartelo, Maryam Aslam, Elisabeth A. Murphy, Caryn R. Hale, Nathalie E. Blachère, Salina Parveen, Edoardo Spolaore, Edward F. DiCarlo, Ellen M. Gravallese, Melanie H. Smith, Accelerating Medicines Partnership RA/SLE Network, Mayu O. Frank, Caroline S. Jiang, Haotan Zhang, Christina Pyrgaki, Myles Lewis, Shafaq Sikandar, Costantino Pitzalis, Joseph B. Lesnak, Khadijah Mazhar, Theodore John Price, Anne‐Marie Malfait, Rachel E. Miller, Fan Zhang, Susan M. Goodman, Robert B. Darnell, Fei Wang, Dana E. Orange, Jennifer S. Albrecht, Jennifer H. Anolik, William A. Apruzzese, Brendan F. Boyce, David L. Boyle, Michael B. Brenner, S. Louis Bridges, Christopher Dominic Buckley, Jane Hoyt Buckner, Vivian P. Bykerk, James Patrick Dolan, Laura T. Donlin, Andrew D. Filer, Gary S. Firestein, Chamith Y. Fonseka, Peter K. Gregersen, Joel M. Guthridge, María Gutiérrez‐Arcelus, V. Michael Holers, Laura B. Hughes, Lionel B. Ivashkiv, Eddie A. James, Judith A. James, Anna Helena Jonsson, Stephen Kelly, James A. Lederer, Yvonne Lee, Arthur M. Mandelin, Mandy J. McGeachy, Joseph Mears, Nida Meednu, Larry W. Moreland, Harris Perlman, Javier Rangel‐Moreno, Deepak A. Rao, Soumya Raychaudhuri, Christopher T. Ritchlin, William H. Robinson, Mina Rohani‐Pichavant, Jennifer A. Seifert, Kamil Slowikowski, Darren Tabechian, Paul J. Utz, Gerald F. Watts, Kevin S. Wei · 发表于：Science Translational Medicine · 年份：2024 · DOI：10.1126/scitranslmed.adk3506 · 被引用次数：69 · 研究领域：Cytokine Signaling Pathways and Interactions、HER2/EGFR in Cancer Research、Rheumatoid Arthritis Research and Therapies

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 l...