title: Inactivation of the Na-Cl co-transporter (NCC) gene is associated with high BMD through both renal and bone mechanisms: analysis of patients with Gitelman syndrome and Ncc null mice.
abstract: Chronic thiazide treatment is associated with high BMD. We report that patients and mice with null mutations in the thiazide-sensitive NaCl cotransporter (NCC) have higher renal tubular Ca reabsorption, higher BMD, and lower bone remodeling than controls, as well as abnormalities in Ca metabolism, mainly caused by Mg depletion.
  
  
  BACKGROUND
  Chronic thiazide treatment decreases urinary Ca excretion (UVCa) and increases BMD. To understand the underlying mechanisms, Ca and bone metabolism were studied in two models of genetic inactivation of the thiazide-sensitive NaCl cotransporter (NCC): patients with Gitelman syndrome (GS) and Ncc knockout (Ncc(-/-)) mice.
  
  
  METHODS
  Ca metabolism was analyzed in GS patients and Ncc(-/-) mice under conditions of low dietary Ca. BMD was measured by DXA in patients and mice, and bone histomorphometry was analyzed in mice.
  
  
  RESULTS
  GS patients had low plasma Mg. They exhibited reduced UVCa, but similar serum Ca and GFR as control subjects, suggesting increased renal Ca reabsorption. Blood PTH was lower despite lower serum ionized Ca, and Mg repletion almost corrected both relative hypoparathyroidism and low UVCa. BMD was significantly increased in GS patients at both lumbar (+7%) and femoral (+16%) sites, and osteocalcin was reduced. In Ncc(-/-) mice, serum Ca and GFR were unchanged, but UVCa was reduced and PTH was elevated; Mg repletion largely corrected both abnormalities. Trabecular and cortical BMD were higher than in Ncc(+/+) mice (+4% and +5%, respectively), and despite elevated PTH, were associated with higher cortical thickness and lower endosteal osteoclastic surface.
  
  
  CONCLUSIONS
  Higher BMD is observed in GS patients and Ncc(-/-) mice. Relative hypoparathyroidism (human) and bone resistance to PTH (mice), mainly caused by Mg depletion, can explain the low bone remodeling and normal/low serum Ca despite increased renal Ca reabsorption.
authors.affiliation: Département de Physiologie, Hôpital Européen George Pompidou, Institut National de la Santé et de la Recherche Médicale INSERM U.652, IFR 58, Université Paris V, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Nicolet-Barousse
authors.forename: Anne
authors.initials: A
authors.lastname: Blanchard
authors.forename: Christian
authors.initials: C
authors.lastname: Roux
authors.forename: Laurence
authors.initials: L
authors.lastname: Pietri
authors.forename: May
authors.initials: M
authors.lastname: Bloch-Faure
authors.forename: Sami
authors.initials: S
authors.lastname: Kolta
authors.forename: Christine
authors.initials: C
authors.lastname: Chappard
authors.forename: Valérie
authors.initials: V
authors.lastname: Geoffroy
authors.forename: Caroline
authors.initials: C
authors.lastname: Morieux
authors.forename: Xavier
authors.initials: X
authors.lastname: Jeunemaitre
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Pierre
authors.initials: P
authors.lastname: Meneton
authors.forename: Michel
authors.initials: M
authors.lastname: Paillard
authors.forename: Pascal
authors.initials: P
authors.lastname: Houillier
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: De Vernejoul
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D001581:Benzothiadiazines; D001835:Body Weight; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D004232:Diuretics; D005260:Female; D006801:Humans; D007011:Hypoparathyroidism; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics*; D008274:Magnesium / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012965:Sodium Chloride / Q000494:pharmacology; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D049992:Sodium Chloride Symporters; D027981:Symporters / Q000737:chemistry* / Q000378:metabolism; D013577:Syndrome; D013829:Thiadiazines / Q000494:pharmacology*; D013977:Tibia / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
chemical_list: D001581:Benzothiadiazines; D004232:Diuretics; D049993:Sodium Chloride Symporter Inhibitors; D049992:Sodium Chloride Symporters; D027981:Symporters; D013829:Thiadiazines; D012965:Sodium Chloride; D008274:Magnesium; D002118:Calcium