In:
Journal of Bone and Mineral Research, Wiley, Vol. 30, No. 1 ( 2015-01), p. 116-127
Abstract:
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 (Ca 2+ ) regulation. We investigated intestinal Ca 2+ absorption and bone Ca 2+ metabolism in nonsense Ncc Ser707X (S707X) homozygous knockin mice (Ncc S707X/S707X mice). Compared to wild‐type and heterozygous knockin littermates, Ncc S707X/S707X mice had increased intestinal absorption of 45 Ca 2+ and expression of the active Ca 2+ transport machinery (transient receptor potential vanilloid 6, calbindin‐D 9K , and plasma membrane Ca 2+ ATPase isoform 1b). Ncc S707X/S707X mice had also significantly increased Ca 2+ 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 Ca 2+ absorption as well as osteoblast differentiation and bone Ca 2+ storage, possibly through a FAK/ERK dependent mechanism. © 2014 American Society for Bone and Mineral Research.
Type of Medium:
Online Resource
ISSN:
0884-0431
,
1523-4681
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
2008867-X
