Objective: Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease that is studied using chronic multifocal osteomyelitis (CMO) mice that develop IL-1β-driven sterile inflammation. The goal of this study was to evaluate the involvement of mast cells in the CMO model and CRMO disease samples. Methods: Histologic and immunostaining of mast cells was performed in CMO and CRMO disease tissues. Genetic ablation of connective tissue mast cells was performed to study their role in CMO disease onset and severity. Immune infiltrates were analyzed using both genetic and pharmacological methods targeting mast cells. Results: Mast cell density was increased in CMO lesions compared to control mice, and genetic ablation of connective tissue mast cells led to significant protection from developing inflammatory bone lesions. Elevated mast cell degranulation and activation was observed in primary cultures of CMO mast cells, and within diseased CMO mice. Treatment of CMO mice with either a mast cell agonist (compound 48/80) or an antagonist (cromolyn) led to altered disease onset and severity. Profiling of human samples from CRMO patients revealed elevated mast cell density in bone biopsies and serum levels of Chymase compared to healthy controls. Conclusion: Together, our results implicate mast cell mediators in promoting sterile inflammation, and rationale for pursuing mast cell-targeted therapies in autoinflammatory diseases.

Aberrant mast cell activation promotes chronic recurrent multifocal osteomyelitis