Gastric acidification plays a key role in regulating the proper calcium levels needed to maintain healthy bones. The study, online this week in Nature Medicine, could have implications in the bone condition osteopetrosis as well as for patients on proton pump inhibitors that are used to treat gastrointestinal diseases such as peptic ulcers.
Osteopetrosis is a condition of pathologically high bone mass. In a subset of these patients there is also evidence of osteopetrorickets - brittle bones due to low calcium levels. Recent evidence has pointed to associations of osteopetrosis with mutations in the TCIRG1 gene, which encodes for a subunit of a proton pump that is required for the proper activity of bone-resorbing cells, called osteoclasts. Michael Amling and colleagues show that Tcirg1 mutant mice have an osteopetrorickets phenotype; whereas, historically, mice mutated in other genes that also control osteoclast activity have only an osteopetrosis phenotype, indicating that these two diseases are distinct.
The team also investigate why osteoclast function is affected in both diseases yet rickets occur in only one and not in the other. They show that Tcirg1 is also expressed in gut cells that control gastric pH levels and that mutant Tcirg1 mice have abnormally high gastric pH. The results suggest that a combination of defects in bone resorption and in gastric pH, likely affecting calcium absorption from the diet, explains the osteopetrorickets phenotype.
This study shows that defects in proton pump activity lead to distinct bone diseases, depending on which cell type is affected. These results could have important clinical implications for patients on proton-pump inhibitors that are used to treat various gastrointestinal conditions, as alterations in gastric pH by these drugs could reduce calcium absorption, weakening their bones.