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Thiazide-Sensitive Na+-Cl- Cotransporter (NCC) Gene Inactivation Results in Increased Duodenal Ca2+ Absorption, Enhanced Osteoblast Differentiation...
Update time:2016-09-11 23:59:00   【 Font: Large  Medium Small

Thiazide-Sensitive Na+-Cl- Cotransporter (NCC) Gene Inactivation Results in Increased Duodenal Ca2+ Absorption, Enhanced Osteoblast Differentiation and Elevated Bone Mineral Density


Inactivation of the thiazide-sensitive sodium chloride cotransporter (NCC) due to genetic mutations in Gitelman’s syndrome (GS) or pharmacological inhibition with thiazide diuretics causes hypocalciuria and increased bone mineral density (BMD) with unclear extrarenal calcium (Ca2+) regulation. We investigated intestinal Ca2+ absorption and bone Ca2+ metabolism in nonsense Ncc Ser707X (S707X) homozygous knockin mice (NccS707X/S707X mice). Compared to wild-type and heterozygous knockin littermates, NccS707X/S707X mice had increased intestinal absorption of 45Ca2+ and expression of the active Ca2+ transport machinery (transient receptor potential vanilloid 6, calbindin-D9K, and plasma membrane Ca2+ ATPase isoform 1b). NccS707X/S707X mice had also significantly increased Ca2+ content accompanied by greater mineral apposition rate (MAR) in their femurs and higher trabecular bone volume, cortical bone thickness, and BMD determined by μCT. Their osteoblast differentiation markers, such as bone alkaline phosphatase, procollagen I, osteocalcin, and osterix, were also significantly increased while osteoclast activity was unaffected. Analysis of marrow-derived bone cells, either treated with thiazide or directly cultured from Ncc S707X knockin mice, showed that the differentiation of osteoblasts was associated with increased phosphorylation of mechanical stress-induced focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). In conclusion, NCC inhibition stimulates duodenal Ca2+ absorption as well as osteoblast differentiation and bone Ca2+ storage, possibly through a FAK/ERK dependent mechanism.


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Source:Journal of Bone and Mineral Research      by Hsu Y J, Yang S S, Cheng C J, et al.
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