title: Impaired gastric acidification negatively affects calcium homeostasis and bone mass.
abstract: Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.
authors.affiliation: Department of Trauma, Hand, and Reconstructive Surgery, Center for Biomechanics and Skeletal Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.forename: Arndt F
authors.initials: AF
authors.lastname: Schilling
authors.forename: Anke
authors.initials: A
authors.lastname: Baranowsky
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seitz
authors.forename: Robert P
authors.initials: RP
authors.lastname: Marshall
authors.forename: Tilman
authors.initials: T
authors.lastname: Linn
authors.forename: Michael
authors.initials: M
authors.lastname: Blaeker
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Matthias
authors.initials: M
authors.lastname: Gebauer
authors.forename: Matthias
authors.initials: M
authors.lastname: Priemel
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.forename: Sandra
authors.initials: S
authors.lastname: Perkovic
authors.forename: Florian
authors.initials: F
authors.lastname: Barvencik
authors.forename: F Timo
authors.initials: FT
authors.lastname: Beil
authors.forename: Andrea
authors.initials: A
authors.lastname: Del Fattore
authors.forename: Annalisa
authors.initials: A
authors.lastname: Frattini
authors.forename: Thomas
authors.initials: T
authors.lastname: Streichert
authors.forename: Klaus
authors.initials: K
authors.lastname: Pueschel
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Rueger
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
authors.forename: Jozef
authors.initials: J
authors.lastname: Zustin
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
mesh_terms: D000143:Acids; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015519:Bone Density / Q000502:physiology*; D001848:Bone Diseases, Developmental / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D006996:Hypocalcemia / Q000150:complications / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D000143:Acids; C484226:Atp6ap1 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; D002118:Calcium