11β-Hydroxysteroid Dehydrogenase Type 1 Facilitates Osteoporosis by Turning on Osteoclastogenesis through Hippo Signaling

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme that transform cortisone to cortisol, which activates the endogenous glucocorticoid function. 11β-HSD1 has been observed to regulate skeletal metabolism, specifically within osteoblasts. However, the function of 11β-HSD1 in osteoclasts has not been elucidated. In this study, we observed increased 11β-HSD1 expression in osteoclasts within an osteoporotic mice model (ovariectomized mice). Then, 11β-HSD1 global knock-out or knock-in mice were employed to demonstrate its function in manipulating bone metabolism, showing significant bone volume decrease in 11β-HSD1 knock-in mice. Furthermore, specifically knock out 11β-HSD1 in osteoclasts, by crossing cathepsin-cre mice with 11β-HSD1(flox/flox) mice, presented significant protecting effect of skeleton when they underwent ovariectomy surgery. In vitro experiments showed the endogenous high expression of 11β-HSD1 lead to osteoclast formation and maturation. Meanwhile, we found 11β-HSD1 facilitated mature osteoclasts formation inhibited bone formation coupled H type vessel (CD31(hi)Emcn(hi)) growth through reduction of PDFG-BB secretion. Finally, transcriptome sequencing of 11β-HSD1 knock in osteoclast progenitor cells indicated the Hippo pathway1 was mostly enriched. Then, by suppression of YAP expression in Hippo signaling, we observed the redundant of osteoclasts formation even in 11β-HSD1 high expression conditions. In conclusion, our study demonstrated the role of 11β-HSD1 in facilitating osteoclasts formation and maturation through the Hippo signaling, which is a new therapeutic target to manage osteoporosis.