Impaired gastric acidification negatively affects calcium homeostasis and bone mass

Proper calcium levels are needed to maintain healthy bones. Michael Amling and his colleagues now show that gastric acidification is a key part of in this process. These findings have possible important clinical implications for patients with osteoporosis and/or those on proton-pump inhibitors, as well as those with a rare genetic disease that causes excess 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 ( pages 610–612 ).