Synovial immune control failure in osteoarthritis: from maintenance of tissue homeostasis to inflammatory niche formation.

Osteoarthritis (OA) is a whole-joint disease involving cartilage, synovium, subchondral bone, and neurovascular structures. Synovitis, damage-associated molecular patterns, and interactions between macrophages and fibroblast-like synoviocytes have been widely studied. However, a tissue-level explanation is still lacking for how low-grade and fluctuating synovial responses become persistent inflammation. We therefore propose a framework of synovial immune control failure. In this framework, the synovium does more than participate in inflammation. By clearing intra-articular damage-related material, limiting the duration of inflammation, maintaining stromal homeostasis, and regulating the entry of peripheral immune cells, it helps determine whether local joint inflammation can return to a low-level state. When damage-related inputs persist and debris clearance, inflammatory resolution, and resetting of cellular states do not occur in parallel, macrophages, fibroblast-like synoviocytes, and the vascular-interstitial interface may form a mutually sustaining pathological cellular network. Disease-associated cellular states and their interactions may then be retained locally in the synovium, forming what this article defines as an inflammatory niche. This niche may form bidirectional feedback with cartilage degeneration and subchondral bone remodeling. However, the synovium is not the common initiating tissue in all patients with OA. This framework may be most relevant to disease subtypes with persistent or recurrent synovitis, myeloid cell activation, and abnormal stromal remodeling. We further discuss the evidence base, boundaries, testable predictions, and potential implications of this model for OA patient stratification and synovium-targeted intervention.