TLR-mediated activation of synovial fibroblasts from osteoarthritis patients promotes chondrocyte dysfunction
- 1German Rheumatology Research Center
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.
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BibTeX
@misc{dai2026tlrmediated,
title = {{TLR-mediated activation of synovial fibroblasts from osteoarthritis patients promotes chondrocyte dysfunction}},
author = {Y. Dai and A. Gong and N. Duran Hernandez and X. Liang and X. Liu and L. J. Gearing and P. Durek and Y. Li and S. Oehme and P. Wu and F. F. Heinrich and K. Lehmann and S. Wu and L. Lauterbach and L. Pichler and T. Maleitzke and S. Donner and C. Perka and E. Latz and G. Kroenke and T. Winkler and M.-F. Mashreghi and M. Loehning and P. Shen},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749398},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749398v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - TLR-mediated activation of synovial fibroblasts from osteoarthritis patients promotes chondrocyte dysfunction
AU - Y. Dai
AU - A. Gong
AU - N. Duran Hernandez
AU - X. Liang
AU - X. Liu
AU - L. J. Gearing
AU - P. Durek
AU - Y. Li
AU - S. Oehme
AU - P. Wu
AU - F. F. Heinrich
AU - K. Lehmann
AU - S. Wu
AU - L. Lauterbach
AU - L. Pichler
AU - T. Maleitzke
AU - S. Donner
AU - C. Perka
AU - E. Latz
AU - G. Kroenke
AU - T. Winkler
AU - M.-F. Mashreghi
AU - M. Loehning
AU - P. Shen
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749398
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749398v1
AB - 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.
ER -