Upregulation of smpd3 via BMP2 stimulation and Runx2

Chae, Young-Mi; Heo, Sun-Hee; Lee, Jae-Mok; Ryoo, Hyun‐Mo; Cho, Je‐Yoel

doi:10.5483/bmbrep.2009.42.2.086

Cited by 24 publications

(35 citation statements)

References 24 publications

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“…In agreement with the strong Smpd3 expression reported in both chondrocytes and osteoblasts, SMPD3 deficiency affects the initiation of mineralization in both cartilage and bone (4,26). It was shown earlier that bone morphogenetic protein (BMP) signaling and chondro-osteogenic transcription factor RUNX2 might be involved in the regulation of Smpd3 expression (24,27). Furthermore, SMPD3 has been shown to act as a negative regulator of chondrocyte hypertrophy in the developing growth plates (24,27).…”

Section: Discussionsupporting

confidence: 54%

“…It was shown earlier that bone morphogenetic protein (BMP) signaling and chondro-osteogenic transcription factor RUNX2 might be involved in the regulation of Smpd3 expression (24,27). Furthermore, SMPD3 has been shown to act as a negative regulator of chondrocyte hypertrophy in the developing growth plates (24,27). In support of the latter finding, we observed an increased deposition of type X collagen, a bona fide marker of the hypertrophic chondrocytes, in the expanded hypertrophic zone of cartilage in the developing fro/fro long bones.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, RUNX2 was shown to affect Smpd3 expression in C2C12 myoblasts (24). In order to identify the regulatory roles of these transcription factors in Smpd3 expression in ATDC5 cells, we examined how their expres- sion is affected by PTHrP signaling.…”

Section: Sox9 Regulates Smpd3 Expression In Chondrocytesmentioning

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: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

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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“…2, C, D and F). Taken together with the evidence that Runx2 directly interacts with and activates the promoter of Smpd3 in C2C12 myoblasts (39), Runx2 seems to be mainly responsible for the spatiotemporal expression of Smpd3 in chondrocytes, in concert with BMP signaling. In addition, it should be noted that the maximum expression of Smpd3/nSMase2 in vivo was observed in bone tissue, where Runx2 is highly expressed.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is currently no information regarding the molecular mechanism for the function of nSMase2 in chondrocyte differentiation. In C2C12 myoblasts, BMP-2-induced Runx2 directly binds to the Smpd3 promoter to up-regulate expression, suggesting that BMP signaling could elevate Smpd3 level in a certain context (39).…”

Section: Although Bone Morphogenic Protein (Bmp) Signaling Promotes Cmentioning

confidence: 99%

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

Kakoi

Maeda

Shinohara

et al. 2014

Journal of Biological Chemistry

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Background: It is not clear how BMP-induced chondrocyte maturation is cell-autonomously terminated. Results: BMP-2 induced the ceramide-generating enzyme neutral sphingomyelinase 2 (nSMase2) in chondrocytes, whereas silencing of nSMase2 enhanced maturation in an Akt signaling-dependent manner. Conclusion: nSMase2 signaling regulates BMP-induced chondrocyte maturation as a negative feedback mechanism. Significance: This study elucidated the novel link between BMP and lipid signaling in chondrogenesis.

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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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Upregulation of smpd3 via BMP2 stimulation and Runx2

Cited by 24 publications

References 24 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

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

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

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