Synovial transcriptional clusters link cartilage degeneration to cell-type-specific gene expression in knee osteoarthritis
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Objectives To identify synovial transcriptional clusters in human knee osteoarthritis (OA) and determine how these relate to synovial histologic features, cell-type-associated gene expression, and cartilage degeneration severity. Methods Bulk RNA sequencing (RNA-seq) of synovial tissue from n = 135 patients with knee OA was analyzed using consensus clustering. Clusters were compared by clinical and histologic features, including cartilage degeneration severity (OARSI score). Single-cell RNA-seq (n = 18) and spatial transcriptomics were used to relate cartilage degeneration-associated gene expression patterns to synovial cell populations. Results Four synovial transcriptional clusters that differed in synovial histologic features and cartilage degeneration severity were identified. Greater cartilage degeneration was associated with enrichment of lining fibroblast- and inflammatory myeloid-associated gene expression, whereas lesser cartilage degeneration was associated with enrichment of sublining fibroblast, endothelial, mural cell, and adipocyte-associated gene expression. Conclusions Human knee OA synovium segregates into transcriptional clusters associated with cartilage degeneration severity. Synovial transcriptional heterogeneity corresponds to cell-type-associated gene expression. Key messages What is already known on this topic Osteoarthritis synovium exhibits marked histologic and molecular heterogeneity. Synovial inflammation detected by MRI correlates with cartilage degeneration and predicts progressive cartilage loss in knee OA. Prior transcriptomic studies have identified molecular subsets of OA synovium, but their relationship to cartilage degeneration severity remains unclear. What this study adds OA synovium segregates into four transcriptional clusters: Sublining (C1), Lymphomyeloid (C2), Myeloid (C3), and Major trauma (C4). Greater cartilage degeneration is associated with enrichment of inflammatory myeloid and lining fibroblast gene expression, whereas lesser degeneration is associated with enrichment of adipocyte, sublining fibroblast, endothelial, and mural cell–associated gene expression. How this study might affect research, practice or policy Provides a framework for a clinically relevant biological stratification of OA patients based on synovial molecular features. Informs future efforts to link synovial biology with OA prognosis, cartilage degeneration, treatment allocation, and development of targeted therapeutic strategies.
Authors: Michael R. Mazzucco, Bella Mehta, Jenelys Ruiz-Ortiz, Caryn Hale, Fuadur Omi, Purva Singh, Ruoxi Yuan, Samantha Lessard, Eun Kyung Song, Mengrui Zhang, Shady Younis, William H. Robinson, Daniel Ramirez, Edward DiCarlo, Wei Wang, Thomas Carroll, Jose Rodriguez, Peter Sculco, Xiaoshun Li, YiYuan Wu, Robert B. Darnell, Martin Lotz, Rachel E. Miller, Tristan Maerz, Anne-Marie Malfait, Accelerating Medicines Partnership: RA/SLE Network (AMP RA/SLE), The RE-JOIN Investigators, Miguel Otero, Dana E. Orange
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Deconstructing Disparities in Lupus Pregnancies, Clinical and Translational Science Center, Mapping the joint-nerve interactome of the knee, Chicago Center on Musculoskeletal Pain (C-COMP) (Overall Application), Osteoarthritis Progression And Sensory Pathway Alterations, Investigating Mucosal Breaks in the Initiation and Progression of Rheumatoid Arthritis, Weill Cornell/Rockefeller/Sloan Kettering MST Program, AIM-for-RA, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success, Molecular Pathways of Pain Generation in Osteoarthritis
OpenAlex ID: W7155570088