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 pathological role in the development of bone fragility, little direct evidence has been found. In order to investigate the pathological 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 the present study, we showed for the first time that in vivo cytoplasmic superoxide caused a distinct weakness in bone stiffness, decreased bone mineral density, aging-like changes in collagen cross-linking, and transcriptional alterations in the genes associated with osteogensis. We also showed that the surface areas of osteoblasts and osteoclasts were significantly decreased 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 the osteoblast number and suppressed RANKL/M-CSF osteoclastgenic 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.

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Zinc (Zn) confers structure and catalytic functions to a number of enzymes and transcription factors, and its homeostasis is tightly controlled by Zn transporters (SLC39/ZIP: importers, SLC30/ZnT: exporters). Zn is an essential trace element, and its deficiency is associated with abnormal endocrine-system reactions leading to vertebral growth retardation and metabolic disorders. However, the molecular mechanisms by which Zn affects the endocrine system remain to be clarified. Here we examined the in vivo roles of SLC39A14, a member of the SLC39 family, by generating its deficient mice. The Slc39a14-knockout (KO) mice exhibit growth retardation accompanied by abnormal chondrocyte differentiation, reduced growth hormone production, and an impaired gluconeogenic program. We found that these phenotypes are attributable to impaired G-protein coupled receptor (GPCR)-mediated signaling, via the parathyroid hormone 1 receptor (PTH1R), growth hormone releasing hormone receptor (GHRHR), and glucagon receptor (GCGR), respectively, due to the degradation of cyclic adenosine monophosphate (cAMP) by the higher phosphodiesterase (PDE) activity in the Slc39a14-KO mice. Thus, the Zn transporter SLC39A14 is a new regulator for GPCR-mediated signaling for systemic growth.

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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the selective loss of upper and lower motoneurons. Approximately 10% of all ALS cases are genetically inherited, and a mutation in the Cu, Zn superoxide dismutase (SOD1) gene is thought to be a cause of motoneuron dysfunction. Importantly, the motoneuron toxicity appears to result from a toxic gain-of-function mutation in SOD1 and not from the loss of superoxide dismutase activity. Transgenic mice overexpressing several types of SOD1 mutant show the ALS-like phenotype and are widely accepted as animal models of ALS. However, no common toxic mechanism has been identified among these SOD1 mutants. Studies using autopsies of ALS patients or model mouse have suggested multiple causes of ALS including oxidative stress, mitochondrial dysfunction, excitotoxicity, neurofilaments abnormality and protein aggregation. Endoplasmic reticulum (ER) stress mediated motoneuron death is also suggested to be included in the pathogenesis of ALS. ALS-related mutant SOD1 evokes ER stress through the specific interaction with Derlin-1, a component of ER associated degradation (ERAD) machinery, leading to the subsequent motoneuron death. Zinc plays an important role in the function of nervous system and its dyshomeostasis is also thought to be one of the causes of ALS. In fact, zinc accumulation is observed in the brains and the spinal cords of mutant SOD1 transgenic mice. Moreover, zinc chelation extends the life span of these mise. There seems to be relationships between zinc dysregulation and several pathogenic processes of ALS. In this review, we will focus on the pathological role of ER stress and zinc in ALS.

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Boron is widely distributed in environment. Recent investigations have been revealed toxicities of inorganic boron-containing compounds. In Sapporo City in Japan, Jyozankei Hot Spring water including high concentration (approximately 40 mg/L) boron has mixed with river water of Toyohira River which is main source of tap water supply (about 98%). In this study, to investigate effects of boron on human health in Sapporo City, seasonal changes of boron concentrations in the river water were investigated in several points. Moreover cell toxicity of boron was investigated using the PC12 cells for 72 hr and 30 days. As the results, the river water contained more than 1.0 mg/L boron was supplied for tap water especially in November. In addition, when over 1.0 mg/L boron was exposed to the cells, cell viabilities decreased significantly. This cell death was considered to be depending on DNA damage due to necrosis by boron treatment.

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Urinary concentrations of inorganic arsenic (iAs) metabolites have been used as biomarker of exposure in the previous studies. However, whether or not iAs and its metabolite concentration in spot urine represents long-term iAs exposure level of the individual has not been extensively studied. The aim of this study was to quantitatively compare inter- and intra-individual variability of urinary iAs metabolites in Japanese subjects for evaluating whether single spot urine is suitable medium for the assessment of long-term iAs exposure. We collected five first morning urine samples from each of 14 healthy female subjects for 4 - 5 months at 2 - 3 weeks interval. Urinary iAs and its metabolites concentrations were determined by liquid chromatography-ICP mass spectrometry with a hydride generation system. The median concentration of iAs + methylarsonic acid in 70 urine samples was 1.90 µg As/g-cre (range: <0.47 - 58.3). The intraclass correlation coefficient of urinary concentration of iAs + methylarsonic acid of the 14 subjects were 0.15, indicating poor reproducibility. It was shown that the concentration of iAs metabolites in single spot urine is not a suitable biomarker of long-term exposure levels of iAs in Japanese at individual level; it was estimated that four spot urine samples were required from a subject for that purpose.

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To confirm whether lanthanum carbonate can be used as a harmless inducer to decrease the bioaccessibility of phosphorus during the digestion process, tissue lanthanum deposition and phosphorus balance as well as liver and kidney functions in serum biochemical tests were examined in rats with long-term dietary administration of lanthanum carbonate. Male 8-week-old Wistar rats were fed a basal diet or the basal diet supplemented with 0.225 or 0.45% lanthanum as lanthanum carbonate for 26 weeks. Lanthanum administration did not influence body and several organ weights as well as liver and kidney functions and iron metabolism in serum biochemical tests. In rats administered lanthanum, a small quantity of lanthanum (200 to 1500 ng/g) was detected in the liver, kidney and femur. Lanthanum was not clearly detected in the brain. Differences in organ lanthanum between 0.225% and 0.45% administration groups were not significant; lanthanum accumulation in the body is low and may be almost saturated to a constant level regardless of the dosage or the period of administration. Lanthanum administration increased fecal phosphorus excretion but did not change serum phosphorus concentration. Equilibrium was maintained in phosphorus balance because urinary phosphorus excretion was decreased in rats with lanthanum administration. Since a serious adverse effect with lanthanum itself was not observed, lanthanum carbonate can be used as a harmless inducer to decrease the bioaccessibility of phosphorus during the digestion process in animal experiments.

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