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

Khavandgar, Zohreh; Poirier, Christophe; Clarke, Christopher J.; Li, Jingjing; Wang, Nicholas; McKee, Marc D.; Hannun, Yusuf A.; Murshed, Monzur

doi:10.1083/jcb.201102051

Cited by 75 publications

(87 citation statements)

References 32 publications

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“…We showed that the restoration of Smpd3 expression in the osteoblasts of fro/fro; Col1a1-Smpd3 mice is sufficient to correct the bone mineralization defects. However, the cartilage abnormalities, which include an expanded zone of hypertrophic chondrocyte-like cells and poor mineralization of the cartilage matrix surrounding these cells in the growth plate, persist in this model (5). These findings suggest that SMPD3 may have distinct roles in bone and cartilage development.…”

Section: Stoffel Et Al Identified the Skeletal Abnormalities In Smpd3mentioning

confidence: 74%

“…Relative gene expression analysis was performed as described previously (21). The primer sequences for Runx2, Sox9, Col10a1, Smpd3, Alpl, Col1a1, and Osx were the same as those published previously (5,21). The primers F2 and R2 mentioned above were used to detect third loxP site expression in the Smpd3 gene.…”

Section: Methodsmentioning

confidence: 99%

“…Samples were scanned at a magnification of ϫ4 (the highest magnification). Micro-CT analyses of the tibias were performed as described previously (5). Long bones (femurs and tibias) were dissected individually and measured with a digital slide caliper (Mastercraft).…”

Section: Methodsmentioning

confidence: 99%

“…Although the skeletal deformities were somewhat similar in the two mouse models, they were more severe in fro/fro mice than in Smpd3 Ϫ/Ϫ mice. Moreover, fro/fro mice showed bone and tooth mineralization defects, which were not investigated in Smpd3 Ϫ/Ϫ mice (5,12). The phenotypic discrepancies between these two mouse models demand further investigation of the tissue-specific roles of SMPD3 during skeletogenesis.…”

Section: Stoffel Et Al Identified the Skeletal Abnormalities In Smpd3mentioning

confidence: 99%

“…Recently, this enzyme has been identified to be a key regulator of skeletal development (2)(3)(4)(5)(6). SMPD3 cleaves sphingomyelin and generates ceramides, a class of lipid second messengers, and phosphocholine, an important intermediate for a number of metabolic pathways (7)(8)(9).…”

mentioning

confidence: 99%

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Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

Manickam

Ray

et al. 2016

Molecular and Cellular Biology

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f Sphingomyelin phosphodiesterase 3 (SMPD3), a lipid-metabolizing enzyme present in bone and cartilage, has been identified to be a key regulator of skeletal development. A homozygous loss-of-function mutation called fragilitas ossium (fro) in the Smpd3 gene causes poor bone and cartilage mineralization resulting in severe congenital skeletal deformities. Here we show that Smpd3 expression in ATDC5 chondrogenic cells is downregulated by parathyroid hormone-related peptide through transcription factor SOX9. Furthermore, we show that transgenic expression of Smpd3 in the chondrocytes of fro/fro mice corrects the cartilage but not the bone abnormalities. Additionally, we report the generation of Smpd3 flox/flox mice for the tissue-specific inactivation of Smpd3 using the Cre-loxP system. We found that the skeletal phenotype in Smpd3 flox/flox ; Osx-Cre mice, in which the Smpd3 gene is ablated in both late-stage chondrocytes and osteoblasts, closely mimics the skeletal phenotype in fro/fro mice. On the other hand, Smpd3 flox/flox ; Col2a1-Cre mice, in which the Smpd3 gene is knocked out in chondrocytes only, recapitulate the fro/fro mouse cartilage phenotype. This work demonstrates that Smpd3 expression in both chondrocytes and osteoblasts is required for normal endochondral bone development. Sphingomyelin phosphodiesterase 3 (SMPD3) is a lipid-metabolizing enzyme present in the membranes of the endoplasmic reticulum and the inner leaflet of the cell membrane (1). Recently, this enzyme has been identified to be a key regulator of skeletal development (2-6). SMPD3 cleaves sphingomyelin and generates ceramides, a class of lipid second messengers, and phosphocholine, an important intermediate for a number of metabolic pathways (7-9).Currently, there are two reported mouse models that lack functional SMPD3. These mouse models have been extensively used to study the physiological roles of this enzyme. Mice in the first model, the fro/fro mouse model, harbor a recessive mutation called fragilitas ossium (fro). It was generated by chemically inducing a deletion in the Smpd3 gene, leading to a complete loss of SMPD3 enzymatic activity (2). The second model, consisting of Smpd3 Ϫ/Ϫ mice, in which Smpd3 was ablated in all the tissues, was generated by a gene-targeting method (2, 10, 11). Stoffel et al. identified the skeletal abnormalities in Smpd3Ϫ/Ϫ mice to be a form of chondrodysplasia (10, 11). Their study suggested that neuronal SMPD3, through systemic means, regulates skeletal development. On the other hand, Aubin et al. reported that the fro mutation results in osteogenesis and dentinogenesis imperfecta (2). Although the skeletal deformities were somewhat similar in the two mouse models, they were more severe in fro/fro mice than in Smpd3 Ϫ/Ϫ mice. Moreover, fro/fro mice showed bone and tooth mineralization defects, which were not investigated in Smpd3 Ϫ/Ϫ mice (5, 12). The phenotypic discrepancies between these two mouse models demand further investigation of the tissue-specific roles of SMPD3 during skeletogenesis.Ou...

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Section: Stoffel Et Al Identified the Skeletal Abnormalities In Smpd3mentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Stoffel Et Al Identified the Skeletal Abnormalities In Smpd3mentioning

confidence: 99%

mentioning

confidence: 99%

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Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

Manickam

Ray

et al. 2016

Molecular and Cellular Biology

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Summarizing craniofacial genetics and developmental biology (SCGDB)

Hall

2014

American J of Med Genetics Pt A

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This overview article highlights active areas of research in craniofacial genetics and developmental biology as reflected in presentations given at the 34th annual meeting of the Society of Craniofacial Genetics and Developmental Biology (SCGDB) in Montreal, Quebec on October 11, 2011. This 1-day meeting provided a stimulating occasion that demonstrated the present status of research in craniofacial genetics and developmental biology and where the field is heading. To accompany the abstracts published in this issue I have selected several themes that emerged from the meeting. After discussing the basis on which craniofacial defects/syndromes are classified and investigated, I address the multi-gene basis of craniofacial syndromes with an examination of the roles of Sox9 and FGF receptors in normal and abnormal craniofacial development. I then turn to the knowledge being gained from population-wide and longitudinal cohort studies and from the discovery of new signaling centers that regulate craniofacial development.

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Increased PHOSPHO1 and alkaline phosphatase expression during the anabolic bone response to intermittent parathyroid hormone delivery

Houston

Stephen

Jayash

et al. 2022

Cell Biochemistry & Function

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The administration of intermittent parathyroid hormone (iPTH) is anabolic to the skeleton. Recent studies with cultured osteoblasts have revealed that the expression of PHOSPHO1, a bone-specific phosphatase essential for the initiation of mineralisation, is regulated by PTH. Therefore, this study sought to determine whether the bone anabolic response to iPTH involves modulation of expression of Phospho1 and of other enzymes critical for bone matrix mineralisation. To mimic iPTH treatment, primary murine osteoblasts were challenged with 50 nM PTH for 6 h in every 48 h period for 8 days (4 cycles), 14 days (7 cycles) and 20 days (10 cycles) in total. The expression of both Phospho1 and Smpd3 was almost completely inhibited after 4 cycles, whereas 10 cycles were required to stimulate a similar response in Alpl expression. To explore the in vivo role of PHOSPHO1 in PTH-mediated osteogenesis, the effects of 14-and 28-day iPTH (80 μg/kg/day) administration was assessed in male wild-type (WT) and Phospho1 −/− mice. The expression of Phospho1, Alpl, Smpd3, Enpp1, Runx2 and Trps1 expression was enhanced in the femora of WT mice following iPTH administration but remained unchanged in the femora of Phospho1 −/− mice. After 28 days of iPTH administration, the anabolic response in the femora of WT was greater than that noted in Phospho1 −/− mice. Specifically, cortical and trabecular bone volume/total volume, as well as cortical thickness, were increased in femora of iPTH-treated WT but not in iPTH-treated Phospho1 −/− mice. Trabecular bone osteoblast number was also increased in iPTH-treated WT mice but not in iPTH-treated Phospho1 −/− mice. The increased levels of Phospho1, Alpl, Enpp1 and Smpd3 in WT mice in response to iPTH administration is consistent with their contribution to the potent anabolic properties of iPTH in bone. Furthermore, as the anabolic response to iPTH was attenuated in

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

Abstract: nSMase2, which cleaves sphingomyelin to generate bioactive lipids, is required for chondrocyte apoptosis and, cell autonomously, for bone mineralization.

Cited by 75 publications

References 32 publications

Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development

Summarizing craniofacial genetics and developmental biology (SCGDB)

Increased PHOSPHO1 and alkaline phosphatase expression during the anabolic bone response to intermittent parathyroid hormone delivery

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