title: A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization.
abstract: A deletion mutation called fro (fragilitas ossium) in the murine Smpd3 (sphingomyelin phosphodiesterase 3) gene leads to a severe skeletal dysplasia. Smpd3 encodes a neutral sphingomyelinase (nSMase2), which cleaves sphingomyelin to generate bioactive lipid metabolites. We examined endochondral ossification in embryonic day 15.5 fro/fro mouse embryos and observed impaired apoptosis of hypertrophic chondrocytes and severely undermineralized cortical bones in the developing skeleton. In a recent study, it was suggested that nSMase2 activity in the brain regulates skeletal development through endocrine factors. However, we detected Smpd3 expression in both embryonic and postnatal skeletal tissues in wild-type mice. To investigate whether nSMase2 plays a cell-autonomous role in these tissues, we examined the in vitro mineralization properties of fro/fro osteoblast cultures. fro/fro cultures mineralized less than the control osteoblast cultures. We next generated fro/fro;Col1a1-Smpd3 mice, in which osteoblast-specific expression of Smpd3 corrected the bone abnormalities observed in fro/fro embryos without affecting the cartilage phenotype. Our data suggest tissue-specific roles for nSMase2 in skeletal tissues.
authors.affiliation: Faculty of Dentistry, McGill University, Montreal, Quebec QC H3A 1A4, Canada.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Khavandgar
authors.forename: Christophe
authors.initials: C
authors.lastname: Poirier
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Clarke
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wang
authors.forename: Marc D
authors.initials: MD
authors.lastname: McKee
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
authors.forename: Monzur
authors.initials: M
authors.lastname: Murshed
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D001842:Bone and Bones / Q000201:enzymology / Q000378:metabolism*; D002113:Calcification, Physiologic; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase