Icariin, a phytoestrogen, exerts rapid estrogenic actions through crosstalk of estrogen receptors in osteoblasts

Abstract

AbstractIcariin, a flavonoid glycoside derived from Epimedium brevicornum Maxim, exerts bone protective effects via estrogen receptors (ERs). This study aimed to investigate the role of ER‐α66, ER‐α36, and GPER in bone metabolism in osteoblasts following treatment with icariin. Human osteoblastic MG‐63 cells and osteoblast‐specific ER‐α66 knockout mice were employed. The ERs crosstalk in the estrogenic action of icariin was evaluated in ER‐α66‐negative human embryonic kidney HEK293 cells. Icariin, like E2, regulated ER‐α36 and GPER protein expression in osteoblasts by downregulating them and upregulating ER‐α66. ER‐α36 and GPER suppressed the actions of icariin and E2 in bone metabolism. However, the in vivo administration of E2 (2 mg/kg/day) or icariin (300 mg/kg/day) restored bone conditions in KO osteoblasts. ER‐α36 and GPER expression increased significantly and rapidly activated and translocated in KO osteoblasts after treatment with E2 or icariin. ER‐α36 overexpression in KO osteoblasts further promoted the OPG/RANKL ratio induced by E2 or icariin treatment. This study showed icariin and E2 elicit rapid estrogenic responses in bone through recruiting ER‐α66, ER‐α36, and GPER. Notably, in osteoblasts lacking ER‐α66, ER‐α36, and GPER mediate the estrogenic effects of icariin and E2, while in intact osteoblasts, ER‐α36 and GPER act as negative regulators of ER‐α66.