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Monday, October 4, 2010

Smpd3

Smpd3 is downregulated by LSJL and is upregulated by axial loading.

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

"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. nSMase2 activity in the brain regulates skeletal development through endocrine factors. 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."

"matrix gla protein (MGP), a small extracellular protein, prevents ECM mineralization in the cartilage and vascular tissues"

"Alpl forced expression in the dermis, a fibrillar, collagen-rich soft connective tissue, resulted in ectopic mineralization of the skin "

"Smpd3 encodes neutral sphingomyelinase 2 (nSMase2), a membrane-bound enzyme, which cleaves sphingomyelin to generate the lipid second messenger ceramide."

"The presence of ALPL activity in the developing fro/fro bones suggests normal PPi hydrolysis in the ECM. However, the PPi levels in the ECM may increase because of an up-regulation of Enpp1 and Ank, which encode two proteins critical for the maintenance of tissue homeostasis of this mineralization inhibitor"

"Smpd3 is highly expressed in bone, and its expression progressively increases as osteoblasts mature."<-The reduction of Smpd3 by LSJL could be a sign of osteogenic matrix degradation allowing for new chondrogenesis.


"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. To study the contribution by combined pituitary hormone deficiency and by the local SMPD3 deficiency in the epiphyseal growth plate to the skeletal phenotype, we introduced the full-length smpd3 cDNA transgene under the control of the chondrocyte-specific promoter Col2a1. A complete rescue of the smpd3(-/-) mouse from severe short-limbed skeletal dysplasia was achieved. The smpd3(-/-) mouse shares its dwarf and chondrodysplasia phenotype with the most common form of human achondrodysplasia, linked to the fibroblast-growth-factor receptor 3 locus, not linked to deficits in the hypothalamic-pituitary epiphyseal growth plate axis. The rescue of smpd3 in vivo has implications for future research into dwarfism and, particularly, growth and development of the skeletal system and for current screening and future treatment of combined dwarfism and chondrodysplasia."

"In wild-type p20 mice, COMP is uniformly distributed throughout the interterritorial extracellular matrix of cartilage. However, even at p20 smpd3−/− mice, COMP immunostaining of cartilage was still restricted to the immediate pericellular matrix of the chondrocytes similar to the COMP distribution in human fetal cartilage"

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