title: Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis.
abstract: Osteocytes are major bone cells that play a crucial role in maintaining the quality of and healing damage to bone tissue. The number of living osteocytes and canalicular networks declines in an age-dependent manner. However, the pathological effects of mitochondrial redox imbalances on osteocytes and bone metabolism have not been fully elucidated. We generated mice lacking mitochondrial superoxide dismutase 2 (Sod2) in osteocytes. Like an aged bone, Sod2 depletion in the osteocytes positively enhanced the production of cellular superoxide in vivo. A bone morphological analysis demonstrated that the Sod2-deficient femurs showed remarkable bone loss in an age-dependent manner. Interestingly, Sod2 loss induced markedly disorganized osteocytic canalicular networks and decreased the number of live osteocytes. Furthermore, Sod2 deficiency significantly suppressed bone formation and increased bone resorption concomitant with the upregulation of sclerostin and receptor activator of NF-κB ligand (RANKL). In vitro experiments also revealed that treatment with paraquat, a superoxide inducer in mitochondria, promoted the RANKL expression via, in part, ERK phosphorylation. These findings demonstrate that the mitochondrial superoxide induced in osteocytes by Sod2 ablation causes age-related bone loss due to the impairment of canalicular networks and bone metabolism via the deregulation of the sclerostin and RANKL expression.
authors.affiliation: 1] Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan [2] Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nojiri
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Saita
authors.affiliation: 1] Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan [2] Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Morikawa
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: 1] Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan [2] Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asou
authors.affiliation: Department of Aging Control Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.affiliation: Department of Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D010011:Osteocytes / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D015854:Up-Regulation; D055114:X-Ray Microtomography; D000099156:Superoxide Dismutase 2
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C486030:Sost protein, mouse