Further, we demonstrate that pharmacologic interventions targeting mast cells at multiple levels reduce the severity of osteoarthritis in mice, including inhibition of (i) the mast cell growth factor receptor c-kit using imatinib (ii) mast cell-derived tryptases using APC366, (iii) IgE-mediated FcεRI-engagement through depletion of IgE, and (iv) FcεRI signaling by inhibiting its downstream signaling molecule Syk. Here, FCER1A is linked to osteoarthritis.