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Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption
Open Access Articles
  • Liang Ye, The Forsyth Institute
  • Leslie R. Morse, Harvard Medical School
  • Li Zhang, The Forsyth Institute
  • Hajime Sasaki, The Forsyth Institute
  • Jason C. Mills, Washington University School of Medicine
  • Paul R. Odgren, University of Massachusetts Medical School
  • Greg Sibbel, Washington University School of Medicine
  • James R.L. Stanley, CBSET Inc
  • Gee Wong, CBSET Inc
  • Ariane Zamarioli, University of São Paulo
  • Ricardo A. Battaglino, The Forsyth Institute
UMMS Affiliation
Department of Cell and Developmental Biology
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Mutations in sorting nexin 10 (Snx10) have recently been found to account for roughly 4% of all human malignant osteopetrosis, some of them fatal. To study the disease pathogenesis, we investigated the expression of Snx10 and created mouse models in which Snx10 was knocked down globally or knocked out in osteoclasts. Endocytosis is severely defective in Snx10-deficient osteoclasts, as is extracellular acidification, ruffled border formation, and bone resorption. We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization. Global Snx10-deficiency in mice results in a combined phenotype: osteopetrosis (due to osteoclast defect) and rickets (due to high stomach pH and low calcium availability, resulting in impaired bone mineralization). Osteopetrorickets, the paradoxical association of insufficient mineralization in the context of a positive total body calcium balance, is thought to occur due to the inability of the osteoclasts to maintain normal calcium-phosphorus homeostasis. However, osteoclast-specific Snx10 knockout had no effect on calcium balance, and therefore led to severe osteopetrosis without rickets. Moreover, supplementation with calcium gluconate rescued mice from the rachitic phenotype and dramatically extended life span in global Snx10-deficient mice, suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized. We conclude that tissue-specific effects of Snx10 mutation need to be considered in clinical approaches to this disease entity. Reliance solely on hematopoietic stem cell transplantation can leave hypocalcemia uncorrected with sometimes fatal consequences. These studies established an essential role for Snx10 in bone homeostasis and underscore the importance of gastric acidification in calcium uptake.

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

DOI of Published Version
PLoS Genet. 2015 Mar 26;11(3):e1005057. doi: 10.1371/journal.pgen.1005057. eCollection 2015. Link to article on publisher's site
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Citation Information
Liang Ye, Leslie R. Morse, Li Zhang, Hajime Sasaki, et al.. "Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption" Vol. 11 Iss. 3 (2015) ISSN: 1553-7390 (Linking)
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