UMMS Affiliation
Department of Cell and Developmental Biology
Publication Date
2015-03-26
Document Type
Article
Disciplines
Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Musculoskeletal Diseases
Abstract
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.
Rights and Permissions
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
10.1371/journal.pgen.1005057
Source
PLoS Genet. 2015 Mar 26;11(3):e1005057. doi: 10.1371/journal.pgen.1005057. eCollection 2015. Link to article on publisher's site
Journal/Book/Conference Title
PLoS genetics
Related Resources
PubMed ID
25811986
Repository Citation
Ye L, Morse LR, Zhang L, Sasaki H, Mills JC, Odgren PR, Sibbel G, Stanley JR, Wong G, Zamarioli A, Battaglino RA. (2015). Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption. Open Access Articles. https://doi.org/10.1371/journal.pgen.1005057. Retrieved from https://escholarship.umassmed.edu/oapubs/2487
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Cell Biology Commons, Cellular and Molecular Physiology Commons, Developmental Biology Commons, Musculoskeletal Diseases Commons