Spatial lipid-barrier coupling in knee osteoarthritis: a mechanism-based perspective centered on the infrapatellar...

Knee osteoarthritis (KOA) is a heterogeneous whole-joint disorder in which mechanical loading, aging, metabolic stress, synovitis, microvascular dysfunction, matrix injury, subchondral remodeling, pain-related neurovascular change, and impaired repair interact over time. The infrapatellar fat pad (IFP) is increasingly recognized as an active synovio-adipose tissue, yet IFP inflammation, lipid disturbance, hypoxia, angiogenesis, matrix catabolism, and subchondral change are often considered parallel abnormalities rather than as a spatially organized propagation process. This Perspective proposes an IFP-centered spatial lipid-barrier coupling framework for a biologically enriched KOA subset. The central claim is not that lipid quantity alone drives KOA, but that lipid-derived signals become mechanistically meaningful when they appear in vulnerable barrier-defined spaces and co-localize with permeability injury, hypoxia, inflammatory execution, oxidative-matrix injury, or impaired repair. In this model, lipid-spatial mislocalization is a candidate threshold event, lipid-cytokine-hypoxia-barrier coupling is the progression engine, and barrier-defined propagation links the IFP, synovium, synovial cavity, cartilage matrix, osteochondral interface, and subchondral marrow-adipose compartment. Current evidence supports active IFP biology, IFP-synovium communication, circulation-to-joint-fluid access, multi-compartment lipid disturbance, HIF/VEGF and FFA-NOX/ROS pathways, and subchondral marrow involvement. However, source-resolved spatial co-localization and temporal ordering remain unproven. The framework should therefore be retained only if a reproducible lipid-barrier signature predicts progression, pain biology, or treatment response beyond synovitis, body mass index, malalignment, bone marrow lesions, and radiographic severity.