Single-cell and spatial transcriptomics analysis of osteoarthritis: pathway regulation, cell interaction networks, and therapeutic translation

Osteoarthritis (OA) transcends the outdated paradigm of mere “wear and tear” cartilage loss. It is now recognized as a complex, whole-organ disease driven by multifaceted interactions among diverse cell populations across synovium, cartilage, subchondral bone, and infrapatellar fat pad. The profound heterogeneity within these tissues and the spatiotemporal dynamics of pathological processes have, until recently, remained a “black box,” limiting our understanding of disease initiation and progression. The convergence of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST) has fundamentally disrupted OA research, offering an unprecedented lens to deconvolute cellular identities, fate decisions, and communication networks within their native architectural context. This review provides a comprehensive critical synthesis of how these high-resolution technologies are redefining the OA pathomechanistic landscape. We first detail the technical underpinnings and comparative advantages of key scRNA-seq and ST platforms, emphasizing burgeoning computational methodologies for their integration. We then articulate how scRNA-seq has deconvoluted the OA joint’s cellular ecosystem, uncovering previously unappreciated states and trajectories. Crucially, we highlight how ST contextualizes these findings, revealing region-specific pathology and defining anatomically precise cross-tissue communication hubs such as the synovium-cartilage axis and the neuro-immune-vascular triad. A dedicated synthesis is given to the spatiotemporal regulation of signaling networks, dissecting core mechanisms of immune dysregulation, neurovascular remodeling, and the novel ECM-mitochondria-mechanics axis. While challenges persist, the path forward is clear. The integration of single-cell and spatial multi-omics is forging a new molecular pathology of OA, defined by cell-state-specific disease drivers rather than broad tissue-level changes. By mapping the precise cellular and spatial coordinates of OA pathogenesis, these technologies are rapidly translating into the discovery of novel, mechanistically grounded therapeutic targets and biomarkers, heralding a future of personalized, interceptive OA medicine.