Beyond a mechanical cushion: the paracrine secretome of the infrapatellar fat pad in knee homeostasis and osteoarthritis.

The Infrapatellar Fat Pad (IFP), traditionally regarded as a passive adipose structure providing mechanical support within the knee, is increasingly recognized as an immunometabolic organ that shapes the intra-articular microenvironment through its paracrine secretome. Understanding these interactions may clarify Osteoarthritis (OA) pathophysiology and inform new diagnostic and therapeutic strategies. This narrative review examined current evidence on the paracrine role of the IFP in knee OA. We focused on its anatomy and cellular composition; cytokines, adipokines, growth factors, matrix-remodeling mediators, and extracellular vesicles; and interactions with cartilage, synovium, subchondral bone, and resident immune cells. Current evidence indicates that the IFP regulates the joint microenvironment through a network of paracrine mediators. Under physiological conditions, its secretome supports tissue homeostasis, repair, and immune regulation. In OA, secretome dysregulation promotes chronic inflammation, extracellular matrix degradation, fibrosis, angiogenesis, and pain sensitization. Emerging findings also suggest that the IFP may provide biomarkers and therapeutic targets for regenerative and disease-modifying strategies. The IFP should be regarded as a biologically active immunometabolic organ involved in knee OA initiation and progression. Better characterization of its secretome may refine OA phenotyping, support biomarker discovery and patient stratification, and guide precision-medicine and disease-modifying approaches.