Molecular Regulatory Mechanism of a Cartilage-Enriched GPCR in Joint Maintenance

PROJECT SUMMARY/ABSTRACT Osteoarthritis (OA) is a leading cause of disability worldwide with no disease-modifying therapies available. One of the hallmarks of OA is cartilage degeneration with abnormal chondrocyte differentiation. It is known that chondrocytes can respond to various signaling via the G protein-coupled receptors (GPCRs), which represent the largest class of targets for drug development. However, due to the lack of relevant animal models, we have a limited understanding of how GPCR-mediated signaling pathways regulate chondrocyte homeostasis and OA pathogenesis. In this project, we will investigate the molecular regulatory mechanisms of a cartilage-enriched GPCR named ADGRG6 in maintaining cartilage and joint homeostasis. Our preliminary studies show that ADGRG6 is highly expressed in healthy cartilage, but its expression is gradually reduced under OA conditions in both human patients and trauma-induced OA mouse models. Loss of Adgrg6 in cartilage lineages leads to OA-like joint structural changes associated with impaired Gs signaling and reduced SOX9 expression. In contrast, overexpression of Adgrg6 in cell cultures leads to a chondroprotective effect in vitro. Based on these findings, we hypothesize that ADGRG6 is required for postnatal joint cartilage maintenance. We will test our hypothesis with three specific aims: in Aim 1, we will investigate the chondrocyte-specific role of ADGRG6 with genetic deletion; in Aim 2, we will elucidate the functional link between ADGRG6/Gs signaling and SOX9 with cell cultures and genetic mouse models; in Aim 3 we will determine if ADGRG6 agonism can protect mice from OA development. Completion of this project will reveal the molecular mechanism of a cartilage-enriched GPCR in regulating joint homeostasis. These insights will support future strategies for targeting GPCRs for OA therapeutics.