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, Hironori; Maeda, Shingo; Shinohara, Naoyuki; Matsuyama, Kanehiro; Imamura, Katsuyuki; Kawamura, Ichiro; Nagano, Satoshi; Setoguchi, Takao; Yokouchi, Masahiro; Ishidou, Yasuhiro; Komiya, Setsuro

doi:10.1074/jbc.m113.509331

Cited by 33 publications

(40 citation statements)

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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: 58%

“…We decided to use this proximal Acan promoter fragment in our transgene because of the similar expression patterns of both Acan and Smpd3 during growth plate development (27,31). In fro/fro; Acan-Smpd3 embryos, although growth plate cartilage mineralization was largely normalized, we did not observe a full correction of the skeletal deformities.…”

Section: Discussionmentioning

confidence: 96%

“…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%

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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: 58%

Section: Discussionmentioning

confidence: 96%

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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“…Runx2 was highly expressed in hypertrophic chondrocytes and osteoblasts [19,27,28], and C/EBPb could enhance Runx2 activity in ossification [21]. The Runx2-dependent expression of sphingomyelin phosphodiesterase 3 (Smpd3) was increased by Bone morphogenic protein 2 (BMP-2) stimulation, and Smpd3 knockdown decreased the apoptosis of terminally matured ATDC5 chondrocytes [33]. Furthermore, Runx2 regulated the differentiation of MSCs as the target of miRNAs [22,23], such as miR-199a ⁄ , a BMP2-responsive miRNA that regulates chondrogenesis via the direct targeting of Smad1 in murine MSCs [35].…”

Section: Discussionmentioning

confidence: 99%

“…Runx2 is an important regulator in chondrogenic differentiation and endochondral ossification, and it was shown that Runx2 regulated endochondral ossification by controlling chondrocyte proliferation and differentiation [1,27,[32][33][34]. Runx2 was highly expressed in hypertrophic chondrocytes and osteoblasts [19,27,28], and C/EBPb could enhance Runx2 activity in ossification [21].…”

Section: Discussionmentioning

confidence: 99%

MiR‐455‐3p regulates early chondrogenic differentiation via inhibiting Runx2

et al. 2015

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Edited by Zhijie ChangKeywords: Chondrogenesis MiR-455-3p Runt-related transcription factor 2 a b s t r a c tThe expression of miR-455-3p has been shown to be up-regulated in chondrogenesis of mesenchymal stem cell, but its role in different stages during chondrogenesis remains unknown. Here, we show that miR-455-3p is increased in ATDC5 cells from 0 d to 21 d, but rapidly decreases at 28 d, and a similar expression kinetic is detected in the development of mouse embryos. We show that miR-455-3p functions as an activator for early chondrogenic differentiation, most likely by inhibiting the expression of Runt-related transcription factor 2 (Runx2) as indicated by luciferase reporter assays. In conclusion, miR-455-3p may activate early chondrogenesis by directly targeting Runx2.

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Chemical Protein Degradation Approach and its Application to Epigenetic Targets

Itoh

2018

The Chemical Record

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In addition to traditional drugs, such as enzyme inhibitors, receptor agonists/antagonists, and protein-protein interaction inhibitors as well as genetic technology, such as RNA interference and the CRISPR/Cas9 system, protein knockdown approaches using proteolysis-targeting chimeras (PROTACs) have attracted much attention. PROTACs, which induce selective degradation of their target protein via the ubiquitin-proteasome system, are useful for the down-regulation of various proteins, including disease-related proteins and epigenetic proteins. Recent reports have shown that chemical protein knockdown is possible not only in cells, but also in vivo and this approach is expected to be used as the therapeutic strategy for several diseases. Thus, this approach may be a significant technique to complement traditional drugs and genetic ablation and will be more widely used for drug discovery and chemical biology studies in the future. In this personal account, a history of chemical protein knockdown is introduced, and its features, recent progress in the epigenetics field, and future outlooks are discussed.

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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

Cited by 33 publications

References 70 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

MiR‐455‐3p regulates early chondrogenic differentiation via inhibiting Runx2

Chemical Protein Degradation Approach and its Application to Epigenetic Targets

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