A Novel Prenylflavonoid Icariside I Ameliorates Estrogen Deficiency-Induced Osteoporosis via Simultaneous Regulation of Osteoblast and Osteoclast Differentiation.

Regulation of osteoblast-mediated bone formation and osteoclast-mediated bone resorption is crucial for bone health. Currently, most clinical drugs for osteoporosis treatment such as bisphosphonates are commonly used to inhibit bone resorption but unable to promote bone formation. In this study, we discovered for the first time that icariside I (GH01), a novel prenylflavonoid isolated from Epimedium , can effectively ameliorate estrogen deficiency-induced osteoporosis with enhancement of trabecular and cortical bone in an ovariectomy (OVX) mouse model. Mechanistically, our in vitro results showed that GH01 repressed osteoclast differentiation and resorption through inhibition of RANKL-induced TRAF6-MAPK-p38-NFATc1 cascade. Simultaneously, we also found that GH01 dose-dependently promoted osteoblast differentiation and formation by inhibiting adipogenesis and accelerating energy metabolism of osteoblasts. In addition, both in vitro and in vivo studies also suggested that GH01 is not only a non-toxic natural small molecule but also beneficial for restoration of liver injury in OVX mice. These results demonstrated that GH01 has great potential for osteoporosis treatment by simultaneous regulation of osteoblast and osteoclast differentiation.