The infrapatellar fat pad-synovium immunometabolic interface in knee osteoarthritis: a local amplifier of joint inflammation.

Knee osteoarthritis (OA) is a whole-joint disease in which synovitis is associated with pain and structural progression. The infrapatellar fat pad (IPFP) lies next to the anterior synovium and contains adipocytes, mesenchymal and fibroblast-like stromal cells, macrophages, vascular cells, and nerves. Alongside its mechanical cushioning role, the IPFP releases adipokines, cytokines, chemokines, lipid mediators, and extracellular vesicles. Adipocyte stress, matrix remodeling, fibrosis, and immune cell accumulation alter this secretory profile in OA. Single-cell analyses of paired human tissues suggest that the IPFP and synovium may share mesenchymal progenitors and undergo coordinated inflammatory and profibrotic remodeling. We propose that these tissues form an immunometabolic interface in which macrophages integrate lipid and damage signals, while stromal cells recruit immune cells and remodel the extracellular matrix (ECM). These interactions may link local metabolic dysfunction to persistent synovitis, cartilage catabolism, and pain. Human evidence, however, comes largely from cross-sectional studies of tissues collected during surgery for advanced OA. Computational predictions of cell-cell communication require functional testing, and animal interventions cannot establish causality in humans. The interface is therefore best regarded as a potential local amplifier of inflammation; its role in disease initiation remains unproven. Longitudinal studies with spatial resolution and interventions stratified by phenotype are needed to determine when, in which patients, and through which components the interface has therapeutic value.