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Prior studies have identified mast cells in the synovial joints of individuals with osteoarthritis1, 2, but the direct participation of mast cells in osteoarthritis remains unknown. Here we identify a central role for mast cells in the pathogenesis of osteoarthritis. Transcriptomic and proteomic analyses of synovial membranes from humans with osteoarthritis and those from individuals without osteoarthritis revealed that mast cell mediators, including mast cell-specific tryptase, are overexpressed in both early-and end-stage osteoarthritis. Using two distinct mouse models of mast cell deficiency, we show that lack of mast cells attenuated osteoarthritis-related pathologies, whereas engraftment of mast cells restored the osteoarthritis phenotype. Pharmacologic inhibition of mast cell maturation or degranulation confirmed the results obtained with genetically-deficient mice. Further, mice deficient in either IgE or its high affinity …