Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization

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Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization. / Stoffel, Wilhelm; Hammels, Ina; Jenke, Britta; Schmidt-Soltau, Inga; Niehoff, Anja.

in: The American journal of pathology, Jahrgang 189, Nr. 9, 11.06.2019, S. 1831-1845.

Publikationen: Beitrag in FachzeitschriftZeitschriftenaufsätzeForschungBegutachtung

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@article{40b1b6046c6048c8902c935169770faa,
title = "Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization",
abstract = "SMPD3 deficiency in the neutral sphingomyelinase (Smpd3-/-) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 as polygenetic determinant of body-height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi-compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiased Smpd3-/- genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but revealed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immuno-histochemistry of long bones of Smpd3-/- mice. A more precise definition of the microarchitecture and three dimensional structure of the bone was asserted by peripheral quantitative computed tomography, high resolution microcomputed tomography, and less precise by dual-energy X-ray absorptiometry for osteodensitometry. Ablation of the Smpd3-locus as part of a 980 kb-deletion on chromosome 8 in the fro/fro mutant, generated by chemical mutagenesis, is held responsible for skeletal hypomineralization, osteoporosis, multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta (OI). The phenotype of the genetically unbiased Smpd3-/- mouse, described here, precludes the proposed role of Smpd3 as a candidate gene of human OI, but suggests SMPD3-deficiency as the pathogenetic basis of a novel form of chondrodysplasia.",
author = "Wilhelm Stoffel and Ina Hammels and Britta Jenke and Inga Schmidt-Soltau and Anja Niehoff",
note = "Copyright {\circledC} 2019. Published by Elsevier Inc.",
year = "2019",
month = "6",
day = "11",
doi = "10.1016/j.ajpath.2019.05.008",
language = "English",
volume = "189",
pages = "1831--1845",
journal = "The American journal of pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "9",

}

RIS

TY - JOUR

T1 - Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization

AU - Stoffel, Wilhelm

AU - Hammels, Ina

AU - Jenke, Britta

AU - Schmidt-Soltau, Inga

AU - Niehoff, Anja

N1 - Copyright © 2019. Published by Elsevier Inc.

PY - 2019/6/11

Y1 - 2019/6/11

N2 - SMPD3 deficiency in the neutral sphingomyelinase (Smpd3-/-) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 as polygenetic determinant of body-height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi-compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiased Smpd3-/- genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but revealed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immuno-histochemistry of long bones of Smpd3-/- mice. A more precise definition of the microarchitecture and three dimensional structure of the bone was asserted by peripheral quantitative computed tomography, high resolution microcomputed tomography, and less precise by dual-energy X-ray absorptiometry for osteodensitometry. Ablation of the Smpd3-locus as part of a 980 kb-deletion on chromosome 8 in the fro/fro mutant, generated by chemical mutagenesis, is held responsible for skeletal hypomineralization, osteoporosis, multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta (OI). The phenotype of the genetically unbiased Smpd3-/- mouse, described here, precludes the proposed role of Smpd3 as a candidate gene of human OI, but suggests SMPD3-deficiency as the pathogenetic basis of a novel form of chondrodysplasia.

AB - SMPD3 deficiency in the neutral sphingomyelinase (Smpd3-/-) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 as polygenetic determinant of body-height. SMPD3 controls homeostasis of the sphingomyelin cycle in the Golgi-compartment, essential for membrane remodeling, initiating multiform vesicle formation and transport in the Golgi secretory pathway. Using the unbiased Smpd3-/- genetic model, this study shows that the perturbed Golgi secretory pathway of chondrocytes of the epiphyseal growth zone leads to dysproteostasis, skeletal growth inhibition, malformation, and chondrodysplasia, but revealed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immuno-histochemistry of long bones of Smpd3-/- mice. A more precise definition of the microarchitecture and three dimensional structure of the bone was asserted by peripheral quantitative computed tomography, high resolution microcomputed tomography, and less precise by dual-energy X-ray absorptiometry for osteodensitometry. Ablation of the Smpd3-locus as part of a 980 kb-deletion on chromosome 8 in the fro/fro mutant, generated by chemical mutagenesis, is held responsible for skeletal hypomineralization, osteoporosis, multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta (OI). The phenotype of the genetically unbiased Smpd3-/- mouse, described here, precludes the proposed role of Smpd3 as a candidate gene of human OI, but suggests SMPD3-deficiency as the pathogenetic basis of a novel form of chondrodysplasia.

U2 - 10.1016/j.ajpath.2019.05.008

DO - 10.1016/j.ajpath.2019.05.008

M3 - Journal articles

C2 - 31199918

VL - 189

SP - 1831

EP - 1845

JO - The American journal of pathology

JF - The American journal of pathology

SN - 0002-9440

IS - 9

ER -

ID: 4200822