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They are characterized by an excessive imbalance of osteoclast formation and activation. During osteolysis, the activation of nuclear factor\u2010\u03baB (NF\u2010\u03baB) and mitogen\u2010activated protein kinase (MAPK) signaling pathways are triggered by receptor activator\u00a0of NF\u2010\u03baB ligand (RANKL), inflammatory factors, and oxidative stress. Previous studies have indicated that the common flavanone glycoside compound hesperetin exhibits anti\u2010inflammatory and antioxidant activity by inhibition of NF\u2010\u03baB and MAPK signaling pathways. However, the direct relationship between hesperetin and osteolysis remain unclear. In the present study, we investigated the effects of hesperetin on lipopolysaccharide (LPS)\u2010induced osteoporosis and elucidated the related mechanisms. Hesperetin effectively suppressed RANKL\u2010induced osteoclastogenesis, osteoclastic bone resorption, and F\u2010actin ring formation in a dose\u2010dependent manner. It also significantly suppressed the expression of osteoclast\u2010specific markers including tartrate\u2010resistant acid phosphatase, matrix metalloproteinase\u20109, cathepsin K, c\u2010Fos, and nuclear factor of activated T\u2010cells cytoplasmic 1. Furthermore, it inhibited osteoclastogenesis by inhibiting activation of NF\u2010\u03baB and MAPK signaling, scavenging reactive oxygen species, and activating the nuclear factor E2 p45\u2010related factor 2\/heme oxygenase 1 (Nrf2\/HO\u20101) signaling pathway. Consistent with in vitro results, hesperetin effectively ameliorated LPS\u2010induced bone loss, reduced osteoclast numbers, and decreased the RANKL\/OPG ratio in vivo. As such, our results suggest that hesperetin may be a great candidate for developing a novel drug for destructive bone diseases such as periodontal disease, tumor bone metastasis, rheumatoid arthritis, and osteoporosis.<\/jats:p>","DOI":"10.1002\/jcp.27924","type":"journal-article","created":{"date-parts":[[2018,12,12]],"date-time":"2018-12-12T05:16:16Z","timestamp":1544591776000},"page":"11009-11022","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Hesperetin suppresses RANKL\u2010induced osteoclastogenesis and ameliorates lipopolysaccharide\u2010induced bone loss"],"prefix":"10.1002","volume":"234","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7206-8747","authenticated-orcid":false,"given":"Hui","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Orthopedics Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan 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