Osteopetrorickets due to Snx10 Deficiency in Mice Results from Both Failed Osteoclast Activity and Loss of Gastric Acid-Dependent Calcium Absorption

• DOI: 10.1371/journal.pgen.1005057
• Publication Date: 2015-03-27T17:17:33Z
• Authors: Liang Ye; Leslie R. Morse; Li Zhang; Hajime Sasaki; Jason C. Mills; Paul R. Odgren; Greg Sibbel; James R. L. Stanley; Gee Wong; Ariane Zamarioli; Ricardo A. Battag...
• Keywords: Osteopetrosis; Bone remodeling

Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some them fatal. To study the disease pathogenesis, we investigated expression Snx10 and created mouse models which was knocked down globally or out osteoclasts. Endocytosis is severely defective Snx10-deficent osteoclasts, as extracellular acidification, ruffled border formation, bone resorption. We also discovered that highly expressed stomach epithelium, with mutations leading high pH low calcium solubilization. Global Snx10-deficiency mice results a combined phenotype: osteopetrosis (due osteoclast defect) rickets availability, resulting impaired mineralization). Osteopetrorickets, paradoxical association insufficient mineralization context positive total body balance, thought occur due inability osteoclasts maintain normal calcium–phosphorus homeostasis. However, osteoclast-specific knockout had no effect on therefore led severe without rickets. Moreover, supplementation gluconate rescued from rachitic phenotype dramatically extended life span global Snx10-deficient mice, suggesting this may be life-saving component clinical approach Snx10-dependent has previously gone unrecognized. conclude tissue-specific effects mutation need considered approaches entity. Reliance solely hematopoietic stem cell transplantation can leave hypocalcemia uncorrected sometimes fatal consequences. These studies established an essential role homeostasis underscore importance gastric acidification uptake.