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: Keiji Kobayashi, Hidetoshi Nojiri, Yoshitomo Saita, Daichi Morikawa, Yusuke Ozawa, Kenji Watanabe, Masato Koike, Yoshinori Asou, Takuji Shirasawa, Koutaro Yokote, Kazuo Kaneko, Takahiko Shimizu
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 9148 (Mar 16 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 25779629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• RANK Ligand
• Sost protein, mouse
• Superoxides
• Superoxide Dismutase
• superoxide dismutase 2

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Bone Resorption (genetics, metabolism)
• Cell Line
• Cell Survival (genetics)
• Disease Models, Animal
• Gene Expression
• Gene Expression Regulation
• Glycoproteins (genetics, metabolism)
• Intercellular Signaling Peptides and Proteins
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Mitochondria (metabolism)
• Osteocytes (metabolism)
• Osteogenesis (genetics)
• Osteoporosis (genetics, metabolism, pathology)
• RANK Ligand (genetics, metabolism)
• Superoxide Dismutase (deficiency, genetics, metabolism)
• Superoxides (metabolism)
• Up-Regulation
• X-Ray Microtomography