Cytoplasmic superoxide causes bone fragility owing to low‐turnover osteoporosis and impaired collagen cross‐linking

• Published in: Journal of bone and mineral research Vol. 26; no. 11; pp. 2682 - 2694
• Main Authors: Nojiri, Hidetoshi, Saita, Yoshitomo, Morikawa, Daichi, Kobayashi, Keiji, Tsuda, Chizuru, Miyazaki, Tsuyoshi, Saito, Mitsuru, Marumo, Keishi, Yonezawa, Ikuho, Kaneko, Kazuo, Shirasawa, Takuji, Shimizu, Takahiko
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2011; Wiley; Oxford University Press
• Subjects: Aging - drug effects; Aging - pathology; Analysis; Animal subjects; Animals; Antioxidants; Ascorbic acid; Ascorbic Acid - administration & dosage; Ascorbic Acid - pharmacology; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone and Bones - pathology; Bone and Bones - physiopathology; Bone fragility; Bone mineral density; Bone Resorption - complications; Bone Resorption - pathology; Bone Resorption - physiopathology; Bone strength; Bones; Cell Count; Cell Survival - drug effects; Collagen; Collagen - metabolism; Connective tissue; Copper; Copper/zinc superoxide dismutase (CuZn‐SOD OR SOD1); Cross-linking; Cross-Linking Reagents - metabolism; Cytoplasm - drug effects; Cytoplasm - metabolism; Fundamental and applied biological sciences. Psychology; Intracellular signalling; Low‐turnover osteoporosis; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - metabolism; Mechanical properties; Mice; Organ Size - drug effects; Osteoblasts; Osteoblasts - drug effects; Osteoblasts - pathology; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - pathology; Osteogenesis; Osteogenesis - drug effects; Osteoporosis - complications; Osteoporosis - metabolism; Osteoporosis - pathology; Osteoporosis - physiopathology; Oxidation-Reduction - drug effects; Oxidative stress; Phenotype; RANK Ligand - metabolism; Reactive oxygen species (ROS); Senescent collagen cross‐links; Signal Transduction - drug effects; Skeleton and joints; Spine; Stress; Superoxide dismutase; Superoxide Dismutase - deficiency; Superoxide Dismutase - metabolism; Superoxides - metabolism; Therapeutic applications; TRANCE protein; Vertebrae; Vertebrates: osteoarticular system, musculoskeletal system; Vitamins; Reactive oxygen species; Enzyme; Glycoprotein; Diseases of the osteoarticular system; Superoxide dismutase; Osteoarticular system; Osteoporosis; Vertebrata; Mammalia; Collagen; BONE FRAGILITY; REACTIVE OXYGEN SPECIES (ROS); Turnover; COPPER/ZINC SUPEROXIDE DISMUTASE (CuZn-SOD OR SOD1); Oxidoreductases; Bone; LOW-TURNOVER OSTEOPOROSIS; SENESCENT COLLAGEN CROSS-LINKS
• DOI: 10.1002/jbmr.489
• ISSN: 0884-0431; 1523-4681

The aging process correlates with the accumulation of cellular and tissue damage caused by oxidative stress. Although previous studies have suggested that oxidative stress plays a pathologic role in the development of bone fragility, little direct evidence has been found. In order to investigate the pathologic significance of oxidative stress in bones, we analyzed the bone tissue of mice deficient in cytoplasmic copper/zinc superoxide dismutase (CuZn‐SOD, encoded by the Sod1 gene; Sod1−/−). In this study, we showed for the first time that in vivo cytoplasmic superoxide caused a distinct weakness in bone stiffness and decreased BMD, aging‐like changes in collagen cross‐linking, and transcriptional alterations in the genes associated with osteogenesis. We also showed that the surface areas of osteoblasts and osteoclasts were decreased significantly in the lumbar vertebrae of Sod1−/− mice, indicating the occurrence of low‐turnover osteopenia. In vitro experiments demonstrated that intracellular oxidative stress induced cell death and reduced the proliferation in primary osteoblasts but not in osteoclasts, indicating that impaired osteoblast viability caused the decrease in osteoblast number and suppressed RANKL/M‐CSF osteoclastogenic signaling in bone. Furthermore, treatment with an antioxidant, vitamin C, effectively improved bone fragility and osteoblastic survival. These results imply that intracellular redox imbalance caused by SOD1 deficiency plays a pivotal role in the development and progression of bone fragility both in vivo and in vitro. We herein present a valuable model for investigating the effects of oxidative stress on bone fragility in order to develop suitable therapeutic interventions. © 2011 American Society for Bone and Mineral Research