title: Dihydroartemisinin attenuates lipopolysaccharide-induced osteoclastogenesis and bone loss via the mitochondria-dependent apoptosis pathway.
abstract: Dihydroartemisinin (DHA) is a widely used antimalarial drug isolated from the plant Artemisia annua. Recent studies suggested that DHA has antitumor effects utilizing its reactive oxygen species (ROS) yielding mechanism. Here, we reported that DHA is inhibitory on lipopolysaccharide (LPS)-induced osteoclast (OC) differentiation, fusion and bone-resorption activity in vitro. Intracellular ROS detection revealed that DHA could remarkably increase ROS accumulation during LPS-induced osteoclastogenesis. Moreover, cell apoptosis was also increased by DHA treatment. We found that DHA-activated caspase-3 increased Bax/Bcl-2 ratio during LPS-induced osteoclastogenesis. Meanwhile, the translocation of apoptotic inducing factor (AIF) and the release of cytochrome c from the mitochondria into the cytosol were observed, indicating that ROS-mediated mitochondrial dysfunction is crucial in DHA-induced apoptosis during LPS-induced osteoclastogenesis. In vivo study showed that DHA treatment decreased OC number, prevents bone loss, rescues bone microarchitecture and restores bone strength in LPS-induced bone-loss mouse model. Together, our findings indicate that DHA is protective against LPS-induced bone loss through apoptosis induction of osteoclasts via ROS accumulation and the mitochondria-dependent apoptosis pathway. Therefore, DHA may be considered as a new therapeutic candidate for treating inflammatory bone loss.
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.|Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, China.
authors.forename: C
authors.initials: C
authors.lastname: Dou
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: N
authors.initials: N
authors.lastname: Ding
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: J
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, China.
authors.forename: F
authors.initials: F
authors.lastname: Kang
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: T
authors.initials: T
authors.lastname: Hou
authors.affiliation: Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, China.
authors.forename: H
authors.initials: H
authors.lastname: Quan
authors.affiliation: Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Dai
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: F
authors.initials: F
authors.lastname: Luo
authors.affiliation: Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biomedical Materials Science, School of Biomedical Engineering, Third Military Medical University, Chongqing 400038, China.|China Orthopedic Regenerative Medicine Group, Chongqing 400038, China.
authors.forename: S
authors.initials: S
authors.lastname: Dong
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D031172:Artemisia annua / Q000737:chemistry / Q000378:metabolism; D037621:Artemisinins / Q000494:pharmacology*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase / Q000235:genetics / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; C039060:artenimol; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse