Seminar: Prof. Joseph G. Verbalis

Hyponatremia-induced Osteoporosis: Cellular Mechanisms and Clinical Significance

Date:
24 January 2013 00:00 hrs.
Location:
Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289
Title:
Hyponatremia-induced Osteoporosis: Cellular Mechanisms and Clinical Significance
Speaker(s):

Prof. Joseph G. Verbalis, Professor of Medicine and Physiology, Chief of Endocrinology and Metabolism, Georgetown University, Washington, USA

 

Host(s):

Prof. Peter Deen, Department of Physiology, NCMLS

24-01-2013 00:00:00Europe/AmsterdamHyponatremia-induced Osteoporosis: Cellular Mechanisms and Clinical Significance Figdor Lecture Theatre, 8th floor RIMLS Building, Geert Grooteplein 26-28, route 289Rimlsrimls@radboudumc.nl

Remarks / more information:

Verbalis, JosephAdaptation to changing extracellular sodium and osmolality is an essential function of all living cells, including bone-resorbing osteoclasts. Recent studies using our rat model of the human disease of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), as well as cross-sectional data from human subjects in NHANES III, have revealed that chronic hyponatremia (serum [Na+] <135 mmol/l) leads to decreased bone mineral content. Cellular and molecular approaches have indicated several potential mechanisms leading to bone loss and osteoporosis with hyponatremia. Assays on murine preosteoclastic RAW264.7 cells and on primary bone marrow monocytes indicated that lowering the medium [Na+] dose-dependently increased osteoclast formation and resorptive activity. Importantly, low [Na+], rather than low osmolality, triggered these effects. Molecular studies indicate that multiple mechanisms may underlie the osteoclastogenic effect of hyponatremia. Chronic reduction of [Na+] dose-dependently decreased intracellular calcium without depleting endoplasmic reticulum calcium stores. Reduction of [Na+] also dose-dependently decreased cellular uptake of radio-labeled ascorbic acid, and reduction of ascorbic acid in the culture medium mimicked the osteoclastogenic effect of low [Na+]. Downstream effects include evidence of hyponatremia-induced oxidative stress as manifested by increased intracellular free oxygen radical accumulation, proportional changes in protein expression and phosphorylation by Western blot analysis of cellular extracts, and increased serum 8-OHdG levelsin vivo in rats. Our results therefore reveal novel sodium signaling mechanisms in osteoclasts that serve to mobilize sodium from bone stores during prolonged hyponatremia, thereby leading to resorptive bone loss and osteoporosis in patients with SIADH. The clinical significance of these findings are that the increased fracture rates found recently in hyponatremic patients is multifactorial, including not only gait instability and increased risk of falls, but also reduced bone quality as a result of  resorptive bone loss and osteoporosis. Bone quality should therefore be assessed in all patients with chronic HN (supported by AG029477). 

References: 

Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, Resnick HE.  Hyponatremia-induced osteoporosis.Journal of Bone and Mineral Research 25(3):554-563, 2010.

Barsony J, Sugimura Y, Verbalis JG.  Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss.J Biological Chemistry 286(12):10864-10875, 2011.

Barsony J, Manigrasso MB, Xu Q, Tam H, Verbalis JG. Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats.Age, 2012, Jan 5 [Epub ahead of print].



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