A groundbreaking study published in the Journal of Orthopaedic Translation unveils the pivotal role of GPR30 activation in inhibiting ferroptosis within chondrocytes by suppressing Yes-associated protein 1 (YAP1) phosphorylation, thus modulating ferritin heavy chain 1 (FTH1) expression. These findings introduce a newer perspective on potential therapeutic interventions for osteoarthritis (OA), presenting G protein-coupled receptor 30 (GPR30) as a novel target for developing treatment strategies.
Dr. Zhao and colleagues explored the molecular landscape of knee OA by analyzing knee specimens from 15 patients undergoing knee replacement surgery. Using cutting-edge techniques such as genome-wide RNA sequencing, western blotting, and immunohistochemistry, the team meticulously examined GPR30 expression levels and ferroptosis-related markers within cartilage tissues obtained from clinical patients. They also evaluated the therapeutic potential of G1, a GPR30 receptor agonist, by studying its effects on OA function and pathology using an animal model. Additionally, chondrocytes were exposed to erastin (a ferroptosis agonist) along with G1, G15 (a GPR30 receptor antagonist), GPR30 short hairpin RNA, or ferrostatin-1 (a ferroptosis inhibitor), followed by the assessment of cell viability and ferroptosis-related indices, as well as the conduct of proteomics analyses.
GPR30 expression exhibited a notable reduction in OA cartilage tissues compared to normal tissues, underscoring its potential involvement in the disease process. Treatment with G1 substantially reduced the locomotor abilities of mice, signifying its therapeutic promise. Additionally, chondrocyte viability witnessed a significant decline following erastin (ferroptosis agonist) treatment; and G1 administration demonstrated a concentration-dependent reduction of this detrimental effect. In addition, the G1 treatment elicited a reduction in phosphorylated YAP1 expression while concurrently increasing activated YAP1 expression levels. This effect was accompanied by enhanced FTH1 transcription and protein expression, indicative of a protective mechanism against ferroptosis.
Articular cartilage, a tissue sensitive to estrogen, expresses both classical nuclear estrogen receptors (ER-α and ER-β) and the novel estrogen membrane receptor known as GPR30, a member of the G protein-coupled receptor family. GPR30, in particular, interacts with estrogen, facilitating quick non-genomic and genomic transcriptional responses, thereby reducing potential estrogen-related side effects. Additionally, research indicates that GPR30 agonism offers a protective effect against mechanical stress-induced chondrocyte apoptosis.
The study findings reveal a significant role for GPR30 in inhibiting YAP1 phosphorylation, thereby regulating FTH1 expression and ultimately hindering chondrocyte ferroptosis. This protective mechanism holds promising implications for OA treatment, highlighting GPR30 as a potential therapeutic target. Notably, this study marks the first demonstration of GPR30’s pivotal role in preventing ferroptosis, further emphasizing its importance in combating OA progression.
Reference
Zhao Z, Niu S, Chen J, Zhang H, Liang L, Xu K, et al. G protein-coupled receptor 30 activation inhibits ferroptosis and protects chondrocytes against osteoarthritis. J Orthop Translat. 2024 Jan;44:125–38.