Impaired gastric acidification negatively affects calcium homeostasis and bone mass.
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.
Schinke
Thorsten
T
Department of Trauma, Hand, and Reconstructive Surgery, Center for Biomechanics and Skeletal Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Schilling
Arndt F
AF
Baranowsky
Anke
A
Seitz
Sebastian
S
Marshall
Robert P
RP
Linn
Tilman
T
Blaeker
Michael
M
Huebner
Antje K
AK
Schulz
Ansgar
A
Simon
Ronald
R
Gebauer
Matthias
M
Priemel
Matthias
M
Kornak
Uwe
U
Perkovic
Sandra
S
Barvencik
Florian
F
Beil
F Timo
FT
Del Fattore
Andrea
A
Frattini
Annalisa
A
Streichert
Thomas
T
Pueschel
Klaus
K
Villa
Anna
A
Debatin
Klaus-Michael
KM
Rueger
Johannes M
JM
Teti
Anna
A
Zustin
Jozef
J
Sauter
Guido
G
Amling
Michael
M
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
D000143:Acids; C484226:Atp6ap1 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; D002118:Calcium