Activation of GPR30 promotes osteogenic differentiation of MC3T3-E1 cells: An implication in osteoporosis

Osteoporosis is an age-related disease characterized by reduced bone volume and disturbed bone metabolism. Novel therapies to rescue or prevent reduced bone mass by guiding the differentiation of pluripotent bone marrow stromal cells away from adipocyte differentiation and toward osteoblastic differentiation may serve as a valuable treatment option against osteoporosis. Estrogen has long been recognized as a key effector of bone formation and mineralization, but the exact mechanisms involved remain poorly understood. In the present study, we investigated the role of the estrogen-specific G protein-coupled receptor 30 (GPR30/GPER) using its specific agonist G1 in MC3T3-E1 preosteoblast cells. Our findings demonstrate that expression of GPR30 is upregulated during osteoblast differentiation and that agonism of GPR30 significantly increases some key markers of mineralization including alkaline phosphatase, osteocalcin, osterix, and type I collagen. We also demonstrate that GPR30 agonism upregulates expression of Runx2, which is recognized as an essential transcription factor involved in bone formation. Additionally, through a series of adenosine monophosphate-activated protein kinase (AMPK)-inhibition experiments using compound C, we show that the positive effects of GPR30 on mineralization and differentiation of preosteoblasts are mediated through the AMPK/anti-acetyl-CoA carboxylase (ACC) pathway. Taken together, the findings of the present study demonstrate the potential of GPR30 as a novel target for the treatment and prevention of osteoporosis.