Discovery of Novel Selective Estrogen Receptor β (SERβ) Agonist ( <i>S</i> )-STO021 as an Antiosteoporosis Candidate with Dual Functions of Inhibiting Osteoclastogenesis and Activating Osteoblastogenesis

Osteoporosis is a systemic and chronic metabolic bone disease of high fracture and mortality. Simultaneous regulation of osteoblast-mediated bone formation and osteoclast-mediated bone resorption has become a potentially effective therapeutic strategy to overcome osteoporosis. Recently, selective activation of estrogen receptor β (SERβ) was demonstrated to promote osteoblast formation and inhibit osteoclast absorption, suggesting that SERβ agonists may be another promising therapeutic approach for treating osteoporosis. Herein, we reported the discovery of a bisphosphonate indanone compound <b>(<i>S</i>)-STO021</b> as a novel SERβ agonist, which exhibited excellent dual functional effects of inhibiting osteoclast resorption and promoting osteoblast formation. Mechanically, the antiosteoporosis efficacy of (<i>S</i>)-STO021 was achieved through inhibiting the TAK1/MKK6/p38 signal and promoting the ERβ/BMP4/SMAD signal. Furthermore, <b>(<i>S</i>)-STO021</b> could not only effectively improve the zebrafish osteoporosis model induced by glucocorticoids but also greatly restore the bone microstructure in ovariectomized rat models. Collectively, our SERβ agonist <b>(<i>S</i>)-STO021</b> could regulate osteoblast and osteoclast differentiation, showing the potential to treat osteoporosis.