Universität zu Köln

Stoffel, Wilhelm, Hammels, Ina, Jenke, Britta, Schmidt-Soltau, Inga and Niehoff, Anja (2019). Neutral Sphingomyelinase 2 (SMPD3) Deficiency in Mice Causes Chondrodysplasia with Unimpaired Skeletal Mineralization. Am. J. Pathol., 189 (9). S. 1831 - 1846. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1525-2191

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Abstract

SMPD3 deficiency in the neutral sphingomyelinase (Smpd3(-/-)) mouse results in a novel form of juvenile dwarfism, suggesting smpd3 is a 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 showed unimpaired mineralization in primary and secondary enchondral ossification centers. This has been elaborated by biochemical analyses and immunohistochemistry of long bones of Smpd3(-/-) mice. A more precise definition of the microarchitecture and three-dimensional structure of the bone was shown by peripheral quantitative computed tomography, high-resolution microcomputed tomography, and less precisely 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, and multiple fractures of long bones, which are hallmarks of human osteogenesis imperfecta. The phenotype of the genetically unbiased Smpd3(-/-)-mouse, described here, precludes the proposed role of Smpd3 as a candidate gene of human osteogenesis imperfecta, but suggests SMPD3 deficiency as the pathogenetic basis of a novel form of chondrodysplasia.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stoffel, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammels, Ina UNSPECIFIED UNSPECIFIED UNSPECIFIED Jenke, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt-Soltau, Inga UNSPECIFIED UNSPECIFIED UNSPECIFIED Niehoff, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-143283
DOI:	10.1016/j.ajpath.2019.05.008
Journal or Publication Title:	Am. J. Pathol.
Volume:	189
Number:	9
Page Range:	S. 1831 - 1846
Date:	2019
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1525-2191
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR-I; ACID; CERAMIDE; APOPTOSIS; HORMONE; MURINE; GENES; ROLES Multiple languages Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14328