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Very few natural products or compounds have been shown to exert therapeutic effects on both OCs and OBs, limiting the potential development of natural compounds for clinical application. Hymenialdisine (HMD) is a marine sponge\u2013derived natural inhibitor of protein kinases with previously reported anti-osteoarthritis and anti-cancer properties. However, the roles of HMD in OCs, OBs, and osteoporosis have not yet been well established. Here, we found that HMD not only suppressed osteoclastogenesis but also promoted OB differentiation. HMD exerted dose-dependent inhibitory effects on RANKL-induced OC formation, bone resorption, and OC-specific gene expression. These strong inhibitory effects were achieved by blocking the NF-\u03baB and MAPK signaling pathways, and NFATc1 expression. In addition, HMD potentially stimulated OB differentiation by activating alkaline phosphatase (ALP) and enhancing OB matrix mineralization. We found that HMD can activate the glycogen synthase kinase 3\u03b2 (GSK-3\u03b2)\/\u03b2-catenin\/T-cell factor (TCF)\/lymphoid enhancer factor (LEF) signaling pathway to upregulate Runx-2 expression, the main transcription factor in this pathway. Increased expression of Runx-2 was also correlated with expression of the OB-specific genes Col1a1 and osteocalcin (Ocn). Furthermore, we also evaluated the therapeutic potential of HMD in a female C57BL\/6j mouse model of ovariectomy (OVX)-induced systematic bone loss. HMD showed a remarkable ability to prevent decreases in bone volume (BV\/TV) and trabecular thickness (Tb.Th). In summary, HMD exerts notable effects in inhibiting OC-related osteolysis and enhancing OB-induced ossification, suggesting the potential application of HMD in osteoporosis treatment. \u00a9 2020 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.4025","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T08:49:33Z","timestamp":1586854173000},"page":"1582-1596","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Hymenialdisine: A Marine Natural Product That Acts on Both Osteoblasts and Osteoclasts and Prevents Estrogen-Dependent Bone Loss in Mice"],"prefix":"10.1093","volume":"35","author":[{"given":"Qingqing","family":"Wang","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences The University of Western Australia Perth WA Australia"},{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Clifford Hospital Jinan University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Western Australia Perth WA Australia"},{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China"},{"name":"Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Western Australia Perth WA Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Western Australia Perth WA Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Kuek","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Western Australia Perth WA Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences The University of Western Australia Perth WA Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3069-9997","authenticated-orcid":false,"given":"Peng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery Clifford Hospital Jinan University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezhi","family":"Song","sequence":"additional","affiliation":[{"name":"Research Centre for Regenerative Medicine and Guangxi Key Laboratory of 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