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Thiazide Diuretics Directly Induce Osteoblast Differentiation and Mineralized Nodule Formation by Interacting with a Sodium Chloride Co-Transporter in Bone

Melita M. Dvorak^*,, Cyrille De Joussineau^*, D. Howard Carter, Trairak Pisitkun, Mark A. Knepper, Gerardo Gamba^||, Paul J. Kemp^* and Daniela Riccardi^*,¶

^* Cardiff University School of Biosciences and ^¶ Cardiff Institute of Tissue Engineering and Repair, Cardiff, United Kingdom; Endocrine Research Unit, Department of Medicine, University of California, San Francisco, California; Turner Dental School, University of Manchester, Manchester, United Kingdom; Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and ^|| Molecular Physiology Unit, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Instituto de Investigaciones Biomedicas Universidad Nacional Autonoma de Mexico, Mexico City, Mexico

Correspondence: Dr. Daniela Riccardi, Cardiff University School of Biosciences, Museum Avenue, Cardiff, CF10 3US, UK. Phone: +44-29-20879132; Fax: +44-29-20874116; E-mail: riccardi{at}cardiff.ac.uk

Received for publication March 22, 2007. Accepted for publication May 22, 2007.

Thiazide diuretics are used worldwide as a first-choice drug for patients with uncomplicated hypertension. In addition to their antihypertensive effect, thiazides increase bone mineral density and reduce the prevalence of fractures. Traditionally, these effects have been attributed to increased renal calcium reabsorption that occurs secondary to the inhibition of the thiazide-sensitive sodium chloride cotransporter (NCC) in the distal tubule. The aim of the current study was to determine whether thiazides exert a direct bone-forming effect independent of their renal action. We found that the osteoblasts of human and rat bone also express NCC, suggesting that these bone-forming cells may be an additional target for thiazides. In vitro, NCC protein was virtually absent in proliferating human and fetal rat osteoblasts, whereas its expression dramatically increased during differentiation. Thiazides did not affect osteoblast proliferation, but directly stimulated the production of the osteoblast differentiation markers runt-related transcription factor 2 (runx2) and osteopontin. Using overexpression/knockdown studies in fetal rat calvarial cells, we show that thiazides increase the formation of mineralized nodules, but loop diuretics do not. Overall, our study demonstrates that thiazides directly stimulate osteoblast differentiation and bone mineral formation independent of their effects in the kidney. Therefore, in addition to their use as antihypertensive drugs, our results suggest that thiazides may find a role in the prevention and treatment of osteoporosis.

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				D. H. Ellison and J. Loffing Thiazide Effects and Adverse Effects: Insights From Molecular Genetics Hypertension, August 1, 2009; 54(2): 196 - 202. [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673