A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse

Abstract

The mouse mutation fragilitas ossium (fro) leads to a syndrome of severe osteogenesis and dentinogenesis imperfecta with no detectable collagen defect. Positional cloning of the locus identified a deletion in the gene encoding neutral sphingomyelin phosphodiesterase 3 (Smpd3) that led to complete loss of enzymatic activity. Our knowledge of SMPD3 function is consistent with the pathology observed in mutant mice and provides new insight into human pathologies.

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

“…Impaired bone mineralization in fro/fro mice fro/fro neonates are characterized by a shortened body stature with skeletal abnormalities (Aubin et al, 2005). As shown by the skeletal preparations of the newborn mice, both flat (intramembranous) and long (endochondral) bones are affected-the parietal suture was poorly mineralized, whereas both fore-and hind limbs were severely bent in the fro/fro mutants (Fig.…”

“…Although these findings established the concurrent requirements of a mineralscaffolding protein matrix and phosphatase activities in skeletal ECM mineralization, they did not rule out the existence of other mechanisms working in concert to regulate this process. A recently identified mutation in a mouse model, which displays altered sphingolipid metabolism and poorly mineralized skeletal tissues, further enforces the likelihood that multiple mechanisms are involved in skeletal mineralization (Guenet et al, 1981;Aubin et al, 2005).…”

“…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.…”

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

“…A deletion mutation in the Smpd3 gene was identified in fragilitas ossium (fro), a mouse model of osteogenesis imperfecta (35). fro/fro mice are characterized by retarded skeletal growth and a severely hypomineralized skeleton with normal osteoblast differentiation; bone mineralization can be rescued by osteoblast-specific overexpression of Smpd3, suggesting an important role of nSMase2 in the mineralization of the extracellular matrix (36).…”