title: Osteopetrorickets due to Snx10 deficiency in mice results from both failed osteoclast activity and loss of gastric acid-dependent calcium absorption.
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.
authors: Department of Mineralized Tissue Biology, The Forsyth Institute, Cambridge, Massachusetts, United States of America; Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America.
authors: Liang
authors: L
authors: Ye
authors: Department of Mineralized Tissue Biology, The Forsyth Institute, Cambridge, Massachusetts, United States of America; Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts, United States of America; Spaulding Rehabilitation Hospital, Boston, Massachusetts.
authors: Leslie R
authors: LR
authors: Morse
authors: Department of Mineralized Tissue Biology, The Forsyth Institute, Cambridge, Massachusetts, United States of America.
authors: Li
authors: L
authors: Zhang
authors: Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America; Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, Massachusetts, United States of America.
authors: Hajime
authors: H
authors: Sasaki
authors: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Jason C
authors: JC
authors: Mills
authors: Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors: Paul R
authors: PR
authors: Odgren
authors: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Greg
authors: G
authors: Sibbel
authors: CBSET Inc, Lexington, Massachusetts, United States of America.
authors: James R L
authors: JR
authors: Stanley
authors: CBSET Inc, Lexington, Massachusetts, United States of America.
authors: Gee
authors: G
authors: Wong
authors: Department of Biomechanics, Medicine and Rehabilitation, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
authors: Ariane
authors: A
authors: Zamarioli
authors: Department of Mineralized Tissue Biology, The Forsyth Institute, Cambridge, Massachusetts, United States of America; Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, United States of America.
authors: Ricardo A
authors: RA
authors: Battaglino
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015519:Bone Density / Q000235:genetics*; D002118:Calcium / Q000008:administration & dosage / Q000378:metabolism; D002125:Calcium Gluconate / Q000008:administration & dosage; D004705:Endocytosis / Q000235:genetics; D005744:Gastric Acid / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006801:Humans; D051379:Mice; D009154:Mutation; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058305:Sorting Nexins / Q000235:genetics* / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C516568:SNX10 protein, human; D058305:Sorting Nexins; D002125:Calcium Gluconate; D002118:Calcium