TLR-mediated activation of synovial fibroblasts from osteoarthritis patients promotes chondrocyte dysfunction
Year: 2026
Type: preprint
Abstract: Objective Toll-like receptor (TLR) activation by cartilage-derived damage-associated molecular patterns contributes to osteoarthritis (OA) pathogenesis, but the role of synovial fibroblasts in this process remains incompletely understood. We investigated the TLR responsiveness of human OA synovial fibroblasts and determined how TLR activation influences fibroblast-mediated regulation of chondrocyte function. Design Primary synovial fibroblasts isolated from OA patients were characterized for TLR expression and stimulated with agonists targeting TLR1/2–TLR9. Inflammatory mediator production, matrix metalloproteinase expression, mitochondrial respiration, and transcriptomic responses were assessed. Functional effects on cartilage homeostasis were evaluated using autologous chondrocyte spheroid co-cultures. Results Approximately 50% of cells within OA synovial membranes were fibroblasts (CD45 - CD31 - PDPN + ). Synovial fibroblasts expressed multiple TLRs at both the transcript and protein levels. Activation of TLR1/2, TLR4, TLR5, and TLR2/6 induced robust expression of IL-6, IL-8, G-CSF, MMP3, and MMP10, with minimal effects on mitochondrial respiratory function. Transcriptomic analysis revealed activation of inflammatory pathways together with enrichment of antigen presentation and protein translation programs. In autologous co-culture, TLR1/2-activated synovial fibroblasts promoted inflammatory and catabolic gene expression, suppressed anabolic gene expression, and impaired chondrocyte spheroid growth. Conclusions Human OA synovial fibroblasts are highly responsive to TLR activation and acquire a pro-inflammatory, cartilage-degrading phenotype that directly impairs chondrocyte homeostasis. These findings identify synovial fibroblasts as key effectors of innate immune signalling within the OA joint and support targeting shared TLR-mediated pathways in joint-resident cells as a potential disease-modifying therapeutic strategy.
Authors: Yujie Dai, Ao Gong, Nayar Durán-Hernández, Xu Liang, Xiaohui Liu, Linden J. Gearing, Pawel Durek, Yonghai Li, Stephan Oehme, Peihua Wu, Frederik F. Heinrich, Katrin Lehmann, Shilei Wu, Luis Lauterbach, Lorenz Pichler, Tazio Maleitzke, Stefanie Donner, Carsten Perka, Eicke Latz, Gerhard Krönke, Tobias Winkler, Mir-Farzin Mashreghi, Max Löhning, Ping Shen
Institutions: Humboldt-Universität zu Berlin, Wuhan Puai Hospital, German Rheumatism Research Centre, Charité – Universitätsmedizin Berlin, Henan Medical University, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Medical University of Vienna, University of Copenhagen, Amager Hospital, Copenhagen University Hospital
Language: English
Subfield: Rheumatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
Award: G7516843693
OpenAlex ID: W7211988798