Machine Learning Reveals Synovial Fibroblast Genes Associated with Pain Affect Sensory Nerve Growth in Rheumatoid Arthritis
Year: 2023
Type: preprint
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 identified a module of 815 genes associated with pain, using a novel machine learning approach, Graph-based Gene expression Module Identification (GbGMI), in samples from patients with longstanding RA, but limited synovial inflammation at arthroplasty, and validated this finding in an independent cohort of synovial biopsy samples from early, untreated RA patients. Single-cell RNA-seq analyses indicated these genes were most robustly expressed by lining layer fibroblasts and receptor-ligand interaction analysis predicted robust lining layer fibroblast crosstalk with pain sensitive CGRP+ dorsal root ganglion sensory neurons. Netrin-4, which is abundantly expressed by lining fibroblasts and associated with pain, significantly increased the branching of pain-sensitive CGRP+ neurons in vitro . We conclude GbGMI is a useful method for identifying a module of genes that associate with a clinical feature of interest. Using this approach, we find that Netrin-4 is produced by synovial fibroblasts in the absence of inflammation and can enhance the outgrowth of CGRP+ pain sensitive nerve fibers. One Sentence Summary Machine Learning reveals synovial fibroblast genes related to pain affect sensory nerve growth in Rheumatoid Arthritis addresses unmet clinical need.
Source: medRxiv
Authors: Zilong Bai, Nicholas Bartelo, Maryam Aslam, Caryn Hale, Nathalie E. Blachere, Salina Parveen, Edoardo Spolaore, Edward DiCarlo, Ellen Gravallese, Melanie H. Smith, Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Mayu O. Frank, Caroline S. Jiang, Haotan Zhang, Myles J. Lewis, Shafaq Sikandar, Costantino Pitzalis, Anne-Marie Malfait, Rachel E. Miller, Fan Zhang, Susan Goodman, Robert Darnell, Fei Wang, Dana E. Orange
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, Foundation for the National Institutes of Health, Arthritis Foundation, Lupus Foundation of America, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Sanofi, Rheumatology Research Foundation, AbbVie, Melvin A. Block Family Foundation, Lupus Research Alliance, Versus Arthritis, National Institutes of Health, Takeda Pharmaceuticals International, Medical Research Council, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Janssen Research and Development
Awards: G1111986450, G1139049665, G1337560105, G1360281539, G173065605, G188243792, G1893349483, G2198129094, G2287249042, G2485223290, G2535366877, G2636385648, G2660462900, G3063912449, G3282597883, Evolving Adaptive and Effector Mechanisms from Pre-RA Through Established Disease, G3657101678, G3668774724, CAREER: Interpretable Deep Modeling of Discrete Time Event Sequences, G4316531433, G4698129410, G4753760760, G4829937125, G5467483533, G5520316217, G5800929693, G6085363542, G6240363391, G6622293001, G668334306, G6791871002, G703087348, G7129837303, G7316078541, G7645249265, G882380370, G9000001696, G9000002510, G9000003399, G9000004833, G9000005140, G9000008302, G9000014358, G9000017462, G9000024915, G9000120489, G9000176611, G9000202655, G9000210567, G9000211905, Osteoarthritis Progression And Sensory Pathway Alterations, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success
OpenAlex ID: W4386090630