Biased agonism of G protein-coupled receptors as a novel strategy for osteoarthritis therapy.

Osteoarthritis (OA) is a prevalent degenerative joint disorder marked by chronic pain, inflammation, and cartilage loss, with current treatments limited to symptom relief. G protein-coupled receptors (GPCRs) play a pivotal role in OA progression by regulating inflammation, chondrocyte survival, and matrix homeostasis. However, their multifaceted signaling, via G proteins or β-arrestins, poses challenges for precise therapeutic targeting. Biased agonism, where ligands selectively activate specific GPCR pathways, emerges as a promising approach to optimize efficacy and reduce side effects. This review examines biased signaling in OA-associated GPCRs, including cannabinoid receptors (CB, CB), chemokine receptors (CCR2, CXCR4), protease-activated receptors (PAR-2), adenosine receptors (AR, AR, AR, AR), melanocortin receptors (MCR, MCR), bradykinin receptors (BR), prostaglandin E receptors (EP-2, EP-4), and calcium-sensing receptors (CaSR). We analyze ligands in clinical trials and explore natural products from Traditional Chinese Medicine as potential biased agonists. These compounds, with diverse structures and bioactivities, offer novel therapeutic avenues. By harnessing biased agonism, this review underscores the potential for developing targeted, safer OA therapies that address its complex pathology, bridging molecular insights with clinical translation.