Osteoprotective Effects Of Estrogen Membrane Receptor GPR30/GPER1 In Ovariectomized Rats

Estrogen plays critical roles in the metabolism of bone. The absorption and turnover of bone would be remarkably elevated in postmenopausal women when the level of estradiol descends expeditiously, which could further lead to lower bone mass and higher fracture risk, and progress to postmenopausal osteoporosis(POP).To be effective, it is necessary for estrogen to bind to its receptors. Till now, there are three estrogen receptors(ERs) identified, namely ERα, ERβ, and G protein-coupled receptor 30(GPR30/GPER1). They have wide distributions in the body, especially the musculoskeletal system and the reproductive system. When patients with osteoporosis are treated with exogenous estrogen for a long time, side effects such as endometrial hyperplasia, uterus and breast tumor would occur.Therefore, the use of the unique characteristics of different estrogen receptors to improve the therapeutic effects and reduce the side effects in estrogen replacement therapy(ERT) has been a vital issue remained to be solved.Previous studies have shown that GPR30/GPER1 may have close relationship with the metabolism of bone in rodent models, however, those focusing mainly on GPR30/GPER1 gene knock-out(GPR30-KO) animals, may not represent the wild-type(WT) ones well.In this study, we examined the effects of GPR30/GPER1 on ovariectomy(OVX)-induced osteoporosis in rats, including the effects on proliferation, differentiation, and expression of proteins in osteoblasts. Administration of G1(35 μg/kg, ip, 3 times/week for 6 weeks), a specific agonist of GPR30/GPER1 or administration of low-dose E2(35 μg/kg, ip, 3 times/week for 6 weeks) combined with G15(160 μg/kg, ip, 3 times/week for 6 weeks), a specific antagonist of GPR30/GPER1 prevented OVX-induced increase in bone turnover rate, decrease in bone mineral content and bone mineral density, damage to bone structure, and aggravation of bone biomechanical properties. In addition, G1 or G15 did not affect uterine weight in the OVX rats. Osteoblasts isolated from calvarias from newborn rats were used to explore the underlying mechanisms. A low concentration of G1(150 pM) promoted proliferation and differentiation of osteoblasts through a positive feedback of GPR30/GPER1, which then activated the PI3K-Akt, ERK, and CREB pathways. G15(750 p M), a specific antagonist of GPR30/GPER1, reversed the above effects initiated by G1 treatment. In conclusion, activation of GPR30/GPER1 when the serum estrogen at a low level or suppression of GPR30/GPER1 when the serum estrogen at a normal level protected bones against osteoporosis in OVX rats and exerted no untoward effect on the uterus. We suggest that GPR30/GPER1 can be used as an effective therapeutic target for the prevention and treatment of postmenopausal osteoporosis.