Adrenergic receptors in osteoarthritis

About This Grant

Abstract Osteoarthritis (OA) is a debilitating disease of the joints involving progressive cartilage degeneration, with no disease modifying therapy available. therefore, it is important to identify novel molecular pathways that can be targeted for OA drug therapy. Sympathetic innervation and receptors characterize OA joint tissues. Although the importance of sympathetic signaling through AR is characterized in skeletal homeostasis, its cartilage-specific role in OA development and progression is largely unknown. Adrenergic receptors are G protein-coupled receptors, their signaling is regulated by the kinase GRK2. We recently demonstrated a key role for GRK2 in diminishing the homeostatic G-protein signal through receptor desensitization in chondrocytes leading to their pathologic differentiation, cartilage degeneration and OA progression. Importantly, we showed that inhibiting GRK2, by genetic deletion or by inhibitory drugs, reverses this process and recovers the homeostatic G-protein signal. However, specific receptors that are desensitized by GRK2 during OA pathogenesis are unknown. Our preliminary data showed decreased b2-AR expression and signaling in OA human and mouse cartilage, with opposite effects of b2-AR stimulation in early and late OA. Altogether, this supports our overarching hypothesis that b2-AR signaling is altered in OA cartilage through GRK2-mediated desensitization, and that correcting this alteration can be a novel therapeutic strategy for OA. To validate our hypothesis, in the first aim we use genetic and pharmacologic manipulations of AR in chondrocytes of DMM mice at early and late phases of OA to determine its role in OA development and progression. In the second aim, we use similar manipulations to determine the role of GRK2- mediated b2-AR desensitization in OA development and progression in OA mice and study the role of b2-AR resensitization in human normal and OA cartilage. These studies will fill a gap in the literature by defining b2-AR regulatory and signaling changes in the joint cartilage during OA, it will enable us to discover a novel therapeutic strategy and targets for OA.