Dermal fibroblasts attenuate osteoarthritis by restoring synovial fibroblast homeostasis.

Background: Managing early-to-mid-stage knee osteoarthritis (OA) remains an unmet clinical need. Synovitis driven by disrupted synovial fibroblast lineage homeostasis is a central pathological driver, but current anti-inflammatory treatments fail to correct this underlying dysfunction. Methods: Fibroblast lineage alterations and phenotypic similarities between dermal fibroblasts (DFbs) and synovial fibroblasts were characterized via synovial single-cell sequencing, histology and transcriptomics. Labeled DFbs were injected into rat knees, with their retention and Results: OA synovium exhibits disrupted fibroblast lineage homeostasis, marked by a prominent pro-inflammatory phenotype in synovial fibroblasts. DFbs shared remarkable phenotypic and transcriptomic similarity with healthy synovial fibroblasts and exhibited intrinsic resistance to inflammatory stimulation. Intra-articularly injected DFbs engrafted specifically in the synovium and persisted for over 3 weeks, producing sustained therapeutic benefits for at least 2 months. Mechanistically, DFbs alleviated cytokine-induced inflammatory responses through paracrine secretion of apolipoprotein D (APOD). Conclusions: This study validates a novel lineage-specific cell therapy for OA that targets synovial fibroblast dysfunction. DFb-based therapy offers a promising disease-modifying strategy for early-to-mid-stage OA, with potential for clinical translation. The Translational Potential of this Article: This article's translational potential lies in validating DFb as a safe and effective cell therapy for rat knee OA, targeting the pathology of disrupted fibroblast lineage homeostasis to alleviate synovitis and cartilage degeneration. It provides a clinically feasible disease-modifying strategy that fills the unmet need for durable OA treatments, laying the groundwork for advancing cell-based therapies into clinical trials.