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Dermal fibroblasts attenuate osteoarthritis by restoring synovial fibroblast homeostasis

ABSTRACT: Background: Managing early-to-mid-stage knee osteoarthritis (OA) remains an unmet clinical need. Synovitis drives OA progression, but current anti-inflammatory therapies offer limited efficacy. Disrupted fibroblast lineage homeostasis is central in chronic inflammation, and targeting this may attenuate synovitis and pathological synovium-cartilage crosstalk in knee OA. Methods: Synovial single-cell sequencing, clinical histological and transcriptomic data assessed fibroblast lineage changes and similarities between dermal fibroblasts (DFb) and synovial fibroblasts. Labeled DFb injection in rat knees evaluated cell retention. Rat anterior cruciate ligament transection (ACLT) model with intra-articular DFb injection assessed the therapeutic efficacy. Co-cultures characterized DFb paracrine effects on synovial fibroblasts and chondrocytes. Proteomics identified active components in DFb supernatants. Results: OA synovium exhibits disrupted fibroblast lineage homeostasis, marked by a prominent pro-inflammatory phenotype in synovial fibroblasts. DFb show high transcriptomic and morphological similarity to synovial fibroblasts from healthy donors. Post-injection, DFb engrafted within the synovium with more than 3-week retention. Intra-articular DFb injection alleviated synovitis and cartilage degeneration in ACLT-induced OA rats. Co-cultures confirmed DFb alleviated cytokine-induced inflammatory responses in synovial fibroblasts and chondrocytes via paracrine mechanisms, and integrated proteomic/transcriptomic analyses identified apolipoprotein D (APOD) as a potential key mediator of these anti-inflammatory effects. Conclusions: This study validates a novel cell therapy for OA that targets disrupted fibroblast lineage homeostasis in synovitis. By modulating pro-inflammatory synovial fibroblasts and alleviating synovitis through restoring lineage homeostasis, DFb ameliorate OA progression, providing a new theoretical basis and practical approach for OA cell therapy research.

ORGANISM(S): Mus musculus

PROVIDER: GSE327818 | GEO | 2026/06/24

REPOSITORIES: GEO

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Project description:Synovial fibroblasts in persistent inflammatory arthritis have been suggested to have parallels with cancer growth and wound healing, both of which involve a stereotypical serum response program. We tested the hypothesis that a serum response program can be used to classify diseased tissues, and investigated the serum response program in fibroblasts from multiple anatomical sites and two diseases. To test our hypothesis we utilized a bioinformatics approach to explore a publicly available microarray dataset including RA, OA and normal synovial tissue, then extended those findings in a new microarray dataset representing matched synovial, bone marrow and skin fibroblasts cultured from RA and OA patients undergoing arthroplasty. The classical fibroblast serum response program discretely classified RA, OA and normal synovial tissues. Analysis of low and high serum treated fibroblast microarray data revealed a hierarchy of control, with anatomical site the most powerful classifier followed by response to serum and then disease. In contrast to skin and bone marrow fibroblasts, exposure of synovial fibroblasts to serum led to convergence of RA and OA expression profiles. Pathway analysis revealed three inter-linked gene networks characterising OA synovial fibroblasts: Cell remodelling through insulin-like growth factors, differentiation and angiogenesis through ?3 integrin, and regulation of apoptosis through CD44. We have demonstrated that Fibroblast serum response signatures define disease at the tissue level, and that an OA specific, serum dependent repression of genes involved in cell adhesion, extracellular matrix remodelling and apoptosis is a critical discriminator between cultured OA and RA synovial fibroblasts. Fibroblasts were isolated from synovium, bone marrow and skin tissue samples taken at the time of knee or hip replacement surgery from 12 rheumatoid arthritis patients meeting the 1987 ACR criteria and 6 osteoarthritis patients diagnosed on the basis of characteristic x-ray findings and the absence of features suggestive of inflammatory arthritis. Only one hip sample was present in either disease group. Fibroblasts were maintained in fibroblast medium (consisting of 81.3% RPMI 1640, 10% FCS, 0.81x MEM non-essential amino acids, 0.81mM sodium orthopyruvate, 1.62mM glutamine, 810U/ml penicillin and 81?g/ml streptomycin) at 37°C in a humidified 5% CO2 atmosphere.

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Dermal fibroblasts attenuate osteoarthritis by restoring synovial fibroblast homeostasis

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