GPR22 is an orphan G protein-coupled receptor with restricted expression in brain and heart 1. It couples constitutively to Gi/o proteins, inhibiting adenylyl cyclase 1, and demonstrates Gi/o-mediated signaling in luciferase reporter assays 2. GPR22 plays a protective cardiovascular role, as GPR22-knockout mice show increased susceptibility to functional decompensation following aortic banding despite normal baseline cardiac structure and function 1. Myocardial GPR22 expression is dramatically reduced under hemodynamic stress 1. Clinically, GPR22 is highly relevant to osteoarthritis: genome-wide association studies identified chromosome 7 variants near GPR22 associated with knee and hand osteoarthritis susceptibility and progression 34. GPR22-positive chondrocytes appear specifically in osteoarthritic cartilage and osteophytes but not in normal articular cartilage 3. GPR22 expression is significantly elevated in osteoarthritic shoulder cartilage compared to cartilage from acute or chr7 instability cases 5. Additionally, GPR22 expression varies abnormally in diabetic tissues 6, and cis-expression quantitative trait loci analysis links GPR22 to juvenile idiopathic arthritis susceptibility 7. These findings establish GPR22 as a potential therapeutic target for osteoarthritis and cardiovascular disease.