title: Bajijiasu Abrogates Osteoclast Differentiation via the Suppression of RANKL Signaling Pathways through NF-κB and NFAT.
abstract: Pathological osteolysis is commonly associated with osteoporosis, bone tumors, osteonecrosis, and chronic inflammation. It involves excessive resorption of bone matrix by activated osteoclasts. Suppressing receptor activator of NF-κB ligand (RANKL) signaling pathways has been proposed to be a good target for inhibiting osteoclast differentiation and bone resorption. Bajijiasu-a natural compound derived fromMorinda officinalisF. C. How-has previously been shown to have anti-oxidative stress property; however, its effect and molecular mechanism of action on osteoclastogenesis and bone resorption remains unclear. In the present study, we found that Bajijiasu dose-dependently inhibited RANKL-induced osteoclast formation and bone resorption from 0.1 mM, and reached half maximal inhibitory effects (IC50) at 0.4 mM without toxicity. Expression of RANKL-induced osteoclast specific marker genes including cathepsin K (Ctsk), nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAcP), vacuolar-type H⁺-ATPase V0 subunit D2 (V-ATPase d2), and (matrix metalloproteinase-2 (MMP2) was inhibited by Bajijiasu treatment. Luciferase reporter gene studies showed that Bajijiasu could significantly reduce the expression and transcriptional activity of NFAT as well as RANKL-induced NF-κB activation in a dose-dependent manner. Further, Bajijiasu was found to decrease the RANKL-induced phosphorylation of extracellular signal-regulated kinases (ERK), inhibitor of κB-α (IκB-α), NFAT, and V-ATPase d2. Taken together, this study revealed Bajijiasu could attenuate osteoclast formation and bone resorption by mediating RANKL signaling pathways, indicative of a potential effect of Bajijiasu on osteolytic bone diseases.
authors.affiliation: The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. gdsthgj@gmail.com.|School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands WA 6009, Australia. gdsthgj@gmail.com.|Orthopedic Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China. gdsthgj@gmail.com.
authors.forename: Guoju
authors.initials: G
authors.lastname: Hong
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands WA 6009, Australia. 20463692@student.uwa.edu.au.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: College of Chinese Materia Medical, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. sxg6902@126.com.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Shi
authors.affiliation: The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. hewei1123@21cn.com.|Orthopedic Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China. hewei1123@21cn.com.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. hipknee@163.com.|Orthopedic Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China. hipknee@163.com.
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
authors.affiliation: The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. weiqshi@126.com.|Orthopedic Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China. weiqshi@126.com.
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. docchen777@gmail.com.|Orthopedic Department, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China. docchen777@gmail.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: College of Chinese Materia Medical, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. booboy@126.com.
authors.forename: Longkai
authors.initials: L
authors.lastname: Qi
authors.affiliation: School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands WA 6009, Australia. jennifer.tickner@uwa.edu.au.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tickner
authors.affiliation: College of Chinese Materia Medical, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. ll76611@126.com.|Artepharm, Co., Ltd., Guangzhou 510000, China. ll76611@126.com.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: The National Key Discipline and the Orthopedic Laboratory, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Jiake.xu@uwa.edu.au.|School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands WA 6009, Australia. Jiake.xu@uwa.edu.au.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004187:Disaccharides / Q000737:chemistry / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D053245:RANK Ligand / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D004187:Disaccharides; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D053245:RANK Ligand; C000588575:fructofuranosyl-(2-2)-fructofuranosyl; D000072000:NF-KappaB Inhibitor alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D025262:Vacuolar Proton-Translocating ATPases
keywords: Bajijiasu; NF-κB; NFAT pathway; RANKL; osteoclast