Our recent animal and human studies revealed that chronic
hyponatremia is a previously unrecognized cause of
osteoporosis that is associated with increased osteoclast numbers in a rat model of the human disease of the syndrome of inappropriate
antidiuretic hormone secretion (
SIADH). We used cellular and molecular approaches to demonstrate that sustained low extracellular
sodium ion concentrations ([Na(+)]) directly stimulate osteoclastogenesis and resorptive activity and to explore the mechanisms underlying this effect. Assays on murine preosteoclastic RAW 264.7 cells and on primary bone marrow monocytes both indicated that lowering the medium [Na(+)] dose-dependently increased osteoclast formation and resorptive activity. Low [Na(+)], rather than low osmolality, triggered these effects. Chronic reduction of [Na(+)] dose-dependently decreased intracellular
calcium without depleting endoplasmic reticulum
calcium stores. Moreover, we found that reduction of [Na(+)] dose-dependently decreased cellular uptake of radiolabeled
ascorbic acid, and reduction of
ascorbic acid in the culture medium mimicked the osteoclastogenic effect of low [Na(+)]. We also detected downstream effects of reduced
ascorbic acid uptake, namely evidence of
hyponatremia-induced oxidative stress. This was manifested by increased intracellular free
oxygen radical accumulation and proportional changes in
protein expression and phosphorylation, as indicated by Western blot analysis from cellular extracts and by increased serum
8-hydroxy-2'-deoxyguanosine levels in vivo in rats. Our results therefore reveal novel
sodium signaling mechanisms in osteoclasts that may serve to mobilize
sodium from bone stores during prolonged
hyponatremia, thereby leading to a resorptive
osteoporosis in patients with
SIADH.