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

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

“…Smpd3 was moderately expressed in cartilage tissue. This expression profile of Smpd3 is essentially similar to the results reported for 2-weekold mice (36). In embryonic bone, we detected prominent expression of Smpd3-coding nSMase2 protein in the bone collar and trabecular bone by immunofluorescence (Fig.…”

“…Indeed, silencing of Smpd3 in mature ATDC5 chondrocytes reduced the number of apoptotic cells (Fig. 6, C and D), suggesting that delayed apoptosis in fro/fro cartilage was a cell-autonomous effect of the loss of function of nSMase2 (36). Because apoptosis of terminally matured hypertrophic chondrocytes is a crucial step in the transition of chondrogenic stage to the bone formation stage in the endochondral ossification system, Smpd3/nSMase2 probably plays a key role in regulating the timing of osteogenesis onset.…”

“…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). Interestingly, the number and area of hypertrophic chondrocytes were significantly increased, and conversion of cartilage into bone was retarded in fro/fro bone.…”

Neutral Sphingomyelinase 2 Deficiency Increases Hyaluronan Synthesis by Up-regulation of Hyaluronan Synthase 2 through Decreased Ceramide Production and Activation of Akt

“…Multiple mouse models for collagenous OI arose spontaneously or have been generated by transgenic techniques. The fragilitas ossium (fro) mouse with a spontaneous deletion in the gene Smpd3 (encoding the active site of NSMase2) is the first mouse model representing noncollagenous OI, displays profound skeletal dysplasia pathologically consistent with OI, and suggests a vital role of NSMase2 in development (5)(6)(7).…”

Osteogenesis Imperfecta

“…The surviving mice have progressive deformity but reduced fracture frequency (Sillence et al, 1993). The underlying mutation is a deletion in the sphingomyelin phosphodiesterase 3 (Smpd3) gene (Aubin et al, 2005) which was recently shown to be a positive regulator of mineralization in in vitro osteoblast cultures (Khavandgar et al, 2011). Mice carrying genetically engineered mutations in Crtap, Lepre1 and Ppib genes encoding the components of the rER heterotrimeric prolyl 3-hydroxylation complex (namely cartilageassociated protein, prolyl 3-hydroxylase 1 and cyclophilin B, respectively) have been generated (Choi et al, 2009;Morello et al, 2006;Vranka et al, 2010).…”