Dystrophin deficiency is associated with muscle inflammation (including mast cell infiltration), as well as osteoporosis. We investigated the role of a G-protein-coupled receptor known as protease-activated receptor-2 (PAR₂) as a potential drug target for Duchenne muscular dystrophy (DMD) by generating PAR₂-null-mdx mice and investigating skeletal, respiratory and cardiac muscles, serum and grip strength every 4 weeks till 20 weeks of age. Tibial trabecular and cortical parameters were also measured at 20 and 32 weeks of age. The results showed a benefit of PAR₂ deletion over time resulting in 27% less diaphragm muscle fibrosis, 45% less muscle fibre necrosis, 41% less muscle fatigue, 88% less serum IL6, 19% less active TGFβ in serum, and 49% lower serum RANKL/OPG ratio in PAR₂-null-mdx mice than mdx mice, with a recovery score of 72% based on serum creatine kinase level at 20 weeks of age. Bone analysis showed an 80% and 18.7% improvement in trabecular BV/TV at 20 and 32 weeks respectively, with a recovery score of 62%. The bone resorption marker CTX1 was 60% and 59% higher in the serum of mdx mice compared to PAR₂-null-mdx mice at 16 and 20 weeks of age, respectively. Interestingly, the number of intact mast cells in the striated muscles of PAR₂-null-mdx mice was twice that of mdx mice, and serum mast cell tryptase concentration was 40% lower in PAR₂-null-mdx mice than mdx mice. These results suggest that PAR₂ activation is involved in mast cell degranulation leading to muscle injury, induction of inflammatory cytokines and the subsequent bone pathology resulting from dystrophin deficiency. This study and the development of pharmacological PAR₂ antagonists suggest that PAR₂ may be a suitable drug target to help ameliorate the clinical effects of dystrophin deficiency.