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Cajaninstilbene acid (CSA) is a natural compound derived from pigeon pea leaves. CSA possesses beneficial properties as an anti\u2010inflammatory, antibacterial, antihepatitis, and anticancer agent; however, its potential to modulate bone homeostasis and osteoporosis has not been studied. We observed that CSA has the ability to suppress RANKL\u2010mediated osteoclastogenesis, osteoclast marker gene expression, and bone resorption in a dose\u2010dependent manner. Mechanistically, it was revealed that CSA attenuates RANKL\u2010activated NF\u2010\u03baB and nuclear factor of activated T\u2010cell pathways and inhibited phosphorylation of key signaling mediators c\u2010Fos, V\u2010ATPase\u2010d2, and ERK. Moreover, in osteoclasts, CSA blocked RANKL\u2010induced ROS activity as well as calcium oscillations. We further evaluated the therapeutic effect of CSA in a preclinical mouse model and showed that in vivo treatment of ovariectomized C57BL\/6 mice with CSA protects the mice from osteoporotic bone loss. Thus, this study demonstrates that osteolytic bone diseases can potentially be treated by CSA.<\/jats:p>","DOI":"10.1002\/jcp.27868","type":"journal-article","created":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T04:51:22Z","timestamp":1543985482000},"page":"11792-11804","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Cajaninstilbene acid inhibits osteoporosis through suppressing osteoclast formation and RANKL\u2010induced signaling pathways"],"prefix":"10.1002","volume":"234","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8935-5374","authenticated-orcid":false,"given":"Youqiang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Orthopedics First Affiliated Hospital, Guangzhou University of Chinese Medicine Guangzhou China"},{"name":"Lingnan Medical Research Center of Guangzhou University of Chinese Medicine Guangzhou China"},{"name":"School of Biomedical Science, The University of 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