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

Autor: Bai Z; Weill Cornell Medicine, New York, NY 10065, USA., Bartelo N; Weill Cornell Medicine, New York, NY 10065, USA., Aslam M; Rockefeller University, New York, NY 10065, USA., Murphy EA; Rockefeller University, New York, NY 10065, USA., Hale CR; Rockefeller University, New York, NY 10065, USA.; Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Blachere NE; Rockefeller University, New York, NY 10065, USA.; Howard Hughes Medical Institute, Rockefeller University, New York, NY 10065, USA., Parveen S; Rockefeller University, New York, NY 10065, USA., Spolaore E; Hospital for Special Surgery, New York, NY 10021, USA., DiCarlo E; Hospital for Special Surgery, New York, NY 10021, USA., Gravallese EM; Brigham and Women's Hospital, Boston, MA 02115, USA., Smith MH; Hospital for Special Surgery, New York, NY 10021, USA., Frank MO; Rockefeller University, New York, NY 10065, USA., Jiang CS; Rockefeller University, New York, NY 10065, USA., Zhang H; Weill Cornell Medicine, New York, NY 10065, USA., Pyrgaki C; Rockefeller University, New York, NY 10065, USA., Lewis MJ; Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London E1 4NS, UK., Sikandar S; Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London E1 4NS, UK., Pitzalis C; Queen Mary University of London & NIHR BRC Barts Health NHS Trust, London E1 4NS, UK.; Department of Biomedical Sciences, Humanitas University & IRCC Humanitas Research Hospital, Milan 20072, Italy., Lesnak JB; University of Texas at Dallas, Richardson, TX 75080, USA., Mazhar K; University of Texas at Dallas, Richardson, TX 75080, USA., Price TJ; University of Texas at Dallas, Richardson, TX 75080, USA., Malfait AM; Rush University Medical Center, Chicago, IL 60612, USA., Miller RE; Rush University Medical Center, Chicago, IL 60612, USA., Zhang F; University of Colorado School of Medicine, Aurora, CO 80045, USA., Goodman S; Hospital for Special Surgery, New York, NY 10021, USA., Darnell RB; Rockefeller University, New York, NY 10065, USA.; Howard Hughes Medical Institute, Rockefeller University, New York, NY 10065, USA., Wang F; Weill Cornell Medicine, New York, NY 10065, USA., Orange DE; Rockefeller University, New York, NY 10065, USA.; Hospital for Special Surgery, New York, NY 10021, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Apr 10; Vol. 16 (742), pp. eadk3506. Date of Electronic Publication: 2024 Apr 10.
DOI: 10.1126/scitranslmed.adk3506
Abstrakt: 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.
Databáze: MEDLINE
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