Journal article
Thiazide-Sensitive Na+-Cl- Cotransporter (NCC) Gene Inactivation Results in Increased Duodenal Ca2+ Absorption, Enhanced Osteoblast Differentiation and Elevated Bone Mineral Density
Journal of bone and mineral research, Vol.30(1), pp.116-127
01/01/2015
DOI: 10.1002/jbmr.2306
PMID: 24984877
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 (Ca2+) regulation. We investigated intestinal Ca2+ absorption and bone Ca2+ 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 Ca-45(2+) and expression of the active Ca2+ transport machinery (transient receptor potential vanilloid 6, calbindin-D-9K, and plasma membrane Ca2+ ATPase isoform 1b). Ncc(S707X/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 CT. 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. (c) 2014 American Society for Bone and Mineral Research.
Details
- Title: Subtitle
- Thiazide-Sensitive Na+-Cl- Cotransporter (NCC) Gene Inactivation Results in Increased Duodenal Ca2+ Absorption, Enhanced Osteoblast Differentiation and Elevated Bone Mineral Density
- Creators
- Yu-Juei Hsu - National Defense Medical CenterSung-Sen Yang - National Defense Medical CenterChih-Jen Cheng - National Defense Medical CenterShu-Ting Liu - National Defense Medical CenterShih-Ming Huang - National Defense Medical CenterTom Chau - Providence St. Vincent Medical CenterPauling Chu - National Defense Medical CenterDonald M. Salter - Institute of GeneticsHerng-Sheng Lee - Kaohsiung Veterans General HospitalShih-Hua Lin - National Defense Medical Center
- Resource Type
- Journal article
- Publication Details
- Journal of bone and mineral research, Vol.30(1), pp.116-127
- Publisher
- Wiley
- DOI
- 10.1002/jbmr.2306
- PMID
- 24984877
- ISSN
- 0884-0431
- eISSN
- 1523-4681
- Number of pages
- 12
- Grant note
- NSC99-2628-B-016-002-MY3; NSC100-2320-B016-006-MY3 / National Science Council-Taiwan; Ministry of Science and Technology, Taiwan TSGH-C99-015-S02; TSGH-C100-011-015-S02 / Tri-Service General Hospital National Research Program for Biopharmaceuticals (NRPB) at the National Science Council (NSC) of Taiwan DOD 100-C02-03; DOD 101-3-5 / Ministry of National Defense-Medical Affairs Bureau
- Language
- English
- Date published
- 01/01/2015
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984383294802771
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