Neutral Sphingomyelinase (SMPD3) Deficiency Causes a Novel Form of Chondrodysplasia and Dwarfism That Is Rescued by Col2A1-Driven smpd3 Transgene Expression

Abstract

Neutral sphingomyelinase SMPD3 (nSMase2), a sphingomyelin phosphodiesterase, resides in the Golgi apparatus and is ubiquitously expressed. Gene ablation of smpd3 causes a generalized prolongation of the cell cycle that leads to late embryonic and juvenile hypoplasia because of the SMPD3 deficiency in hypothalamic neurosecretory neurons. We show here that this novel form of combined pituitary hormone deficiency is characterized by the perturbation of the hypothalamus-pituitary growth axis, associated with retarded chondrocyte development and enchondral ossification in the epiphyseal growth plate.

A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization

“…However, Stoffel et al (2005Stoffel et al ( , 2007, in their gene-targeted model, did not observe bone and tooth mineralization abnormalities, which are seen in all fro/fro mice. This apparent discrepancy can be explained by differences in the analytical methods used to characterize the two mouse lines.…”

“…Further insight into the functions of this enzyme came with the development of animal models lacking nSMase2 activity. Currently, there are two nSMase2-deficient mouse models available: one was generated by gene targeting (Smpd3 / ), whereas the other carries a chemically induced deletion of 1,758 bp encompassing part of intron 8 and the adjacent exon 9 of the Smpd3 gene (Aubin et al, 2005;Stoffel et al, 2005Stoffel et al, , 2007. The latter mutation known as fragilitas ossium or fro replaces the last 33 amino acids of nSMase2, resulting in a significant reduction of total neutral sphingomyelinase activities in the tissues of the fro/fro mice (Aubin et al, 2005;Stoffel et al, 2005Stoffel et al, , 2007.…”

“…Currently, there are two nSMase2-deficient mouse models available: one was generated by gene targeting (Smpd3 / ), whereas the other carries a chemically induced deletion of 1,758 bp encompassing part of intron 8 and the adjacent exon 9 of the Smpd3 gene (Aubin et al, 2005;Stoffel et al, 2005Stoffel et al, , 2007. The latter mutation known as fragilitas ossium or fro replaces the last 33 amino acids of nSMase2, resulting in a significant reduction of total neutral sphingomyelinase activities in the tissues of the fro/fro mice (Aubin et al, 2005;Stoffel et al, 2005Stoffel et al, , 2007. In their recent studies, Stoffel et al (2005Stoffel et al ( , 2007 characterized the skeletal phenotypes of the Smpd3 / mice as a chondrodysplasia and speculated a systemic role for neuronal Smpd3 in the regulation of the skeletal development.…”

“…The latter mutation known as fragilitas ossium or fro replaces the last 33 amino acids of nSMase2, resulting in a significant reduction of total neutral sphingomyelinase activities in the tissues of the fro/fro mice (Aubin et al, 2005;Stoffel et al, 2005Stoffel et al, , 2007. In their recent studies, Stoffel et al (2005Stoffel et al ( , 2007 characterized the skeletal phenotypes of the Smpd3 / mice as a chondrodysplasia and speculated a systemic role for neuronal Smpd3 in the regulation of the skeletal development. Although both the Smpd3 / and fro/fro mutants show similar gross skeletal abnormalities, some phenotypic differences exist between these two models.…”

“…This apparent discrepancy can be explained by differences in the analytical methods used to characterize the two mouse lines. Stoffel et al (2005Stoffel et al ( , 2007 analyzed the mineralization status of the Smpd3 / mice solely by bone mineral density analysis, which determines the total bone mineral content and is not suitable for detecting an increase in unmineralized bone matrix. In contrast, we analyzed the fro/fro bones using a histomorphometric technique on undecalcified samples, commonly used to detect skeletal mineralization defects.…”