Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis - PubMed (original) (raw)
. 2024 Apr 10;16(742):eadk3506.
doi: 10.1126/scitranslmed.adk3506. Epub 2024 Apr 10.
Nicholas Bartelo 1, Maryam Aslam 2, Elisabeth A Murphy 2, Caryn R Hale 2 3, Nathalie E Blachere 2 4, Salina Parveen 2, Edoardo Spolaore 5, Edward DiCarlo 5, Ellen M Gravallese 6, Melanie H Smith 5; Accelerating Medicines Partnership RA/SLE Network; Mayu O Frank 2, Caroline S Jiang 2, Haotan Zhang 1, Christina Pyrgaki 2, Myles J Lewis 7, Shafaq Sikandar 7, Costantino Pitzalis 7 8, Joseph B Lesnak 9, Khadijah Mazhar 9, Theodore J Price 9, Anne-Marie Malfait 10, Rachel E Miller 10, Fan Zhang 11, Susan Goodman 5, Robert B Darnell 2 4, Fei Wang 1, Dana E Orange 2 5
Collaborators, Affiliations
- PMID: 38598614
- DOI: 10.1126/scitranslmed.adk3506
Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis
Zilong Bai et al. Sci Transl Med. 2024.
Abstract
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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