Dermal fibroblasts attenuate osteoarthritis by restoring synovial fibroblast homeostasis

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.