Mitochondrial superoxide in osteocytes perturbs canalicular networks in the setting of age-related osteoporosis

• Published in: Scientific reports Vol. 5; no. 1; p. 9148
• Main Authors: Kobayashi, Keiji, Nojiri, Hidetoshi, Saita, Yoshitomo, Morikawa, Daichi, Ozawa, Yusuke, Watanabe, Kenji, Koike, Masato, Asou, Yoshinori, Shirasawa, Takuji, Yokote, Koutaro, Kaneko, Kazuo, Shimizu, Takahiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-03-2015; Nature Publishing Group
• Subjects: 147/135; 38/88; 42/41; 631/80/304; 64/60; 692/699/2743/316/801; Age; Animals; Bone growth; Bone healing; Bone loss; Bone resorption; Bone Resorption - genetics; Bone Resorption - metabolism; Bone turnover; Cell Line; Cell Survival - genetics; Deregulation; Disease Models, Animal; Gene Expression; Gene Expression Regulation; Glycoproteins - genetics; Glycoproteins - metabolism; Humanities and Social Sciences; Male; Metabolism; Mice; Mice, Knockout; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; multidisciplinary; Osteocytes; Osteocytes - metabolism; Osteogenesis; Osteogenesis - genetics; Osteoporosis; Osteoporosis - genetics; Osteoporosis - metabolism; Osteoporosis - pathology; Paraquat; Phosphorylation; RANK Ligand - genetics; RANK Ligand - metabolism; Science; SOST protein; Superoxide dismutase; Superoxide Dismutase - deficiency; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxides - metabolism; TRANCE protein; Up-Regulation; X-Ray Microtomography
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep09148

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.