Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice

Stein, Merle; Barnea-Zohar, Maayan; Shalev, Moran; Arman, Esther; Brenner, Ori; Winograd-Katz, Sabina; Gerstung, Jennifer; Thalji, Fadi; Kanaan, Moien; Elinav, Hila; Stepensky, Polina; Geiger, Benjamin; Tuckermann, Jan; Elson, Ari

Affiliations

¹Institute of Comparative Molecular Endocrinology, University of Ulm, 89081 Ulm, Germany

²Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel

³Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot 76100, Israel

⁴Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel

⁵Istishari Arab Hospital, Ramallah, Palestine

⁶Hereditary Research Laboratory and Department of Life Sciences, Bethlehem University, Bethlehem, Palestine

⁷Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

⁸Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Abstract and keywords

The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan. Osteopetrosis in this model is the result of osteoclast inactivity that, in turn, is caused by absence of ruffled borders in the mutant osteoclasts and by their inability to secrete protons. These results confirm that the R51Q mutation in SNX10 is a causative factor in ARO and provide a model system for studying this rare disease.

Keywords: Osteoclast; SNX10; Sorting nexin 10; Osteopetrosis; Autosomal recessive osteopetrosis; +/+; wild-type; ARO; autosomal recessive osteopetrosis; CTX; type I C-terminal collagen telopeptides; HSCT; hematopoietic stem cell transplantation; M-CSF; macrophage colony stimulating factor; OB; osteoblast; OCL; osteoclast; P1NP; type 1 collagen N-terminal propeptide; PTH; parathyroid hormone; RANK; receptor activator of nuclear factor kappa-Β; RANKL; RANK ligand; RQ/+; heterozygous for the R51Q mutation in SNX10; RQ/RQ; homozygous for the R51Q mutation in SNX10; SNX10; sorting nexin 10

Links

DOI: 10.1016/j.bone.2020.115360

PubMed: 32278070

WoS: 000535131500019

History

Received: 2020-01-13

Revised: 2020-04-6

Accepted: 2020-04-6

Online: 2020-04-8

Cited Works (2)

Year	Entry
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Cited By (1)

Year	Entry
2022	Huybrechts Y, Van Hul W. Osteopetrosis associated with PLEKHM1 and SNX10 genes, both involved in osteoclast vesicular trafficking. Bone. November 2022;164:116520.