Abstract: Osteophytes are a prominent feature of osteoarthritis (OA) pathology. RNA-seq of osteophytes revealed patterns corresponding to active ECM re-modulation and participation of mast cells. The cells recruitment and their activity status were confirmed by anti-TPSAB1 and anti-FC epsilon RI antibodies in immunohistochemistry. Besides subchondral bone, which is a logical yet unproven route for the cells deployment into osteophytes, the authors propose that OA synovial fluid (SF) is necessary and sufficient for maturation of mast cell precursors (MCPs) in this channel. The authors present evidences to support their claim in the form of IHC, proteomics analysis of SF samples and in vitro cell differentiation assay, wherein human monocytes (ThP1) and hematopoietic stem cells (HSCs) showed differentiation in HLA-DR+/CD206+ and FCERI+ phenotype respectively after 9 days of SF treatment. These observations expound osteophytes and resident mast cells as yet unexplained functional epicentre in OA pathology.