ArticleThe Journal of biological chemistry2014
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.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 34 citations in OpenAlex.
- A Review Discussing Synthesis and Translational Studies of Medicinal Agents Targeting Sphingolipid Pathways.Biomolecules · 2025Review
- Neutral sphingomyelinase 2: A promising drug target for CNS disease.Advances in pharmacology (San Diego, Calif.) · 2025Review
- Extracellular Vesicle-Derived circITGB1 Regulates Dendritic Cell Maturation and Cardiac Inflammation via miR-342-3p/NFAM1.Oxidative medicine and cellular longevity · 2022Article
- A Pilot Study of Seamless Regeneration of Bone and Cartilage in Knee Joint Regeneration Using Honeycomb TCP.Materials (Basel, Switzerland) · 2021Article
- Trabecular Bone Parameters, TIMP-2, MMP-8, MMP-13, VEGF Expression and Immunolocalization in Bone and Cartilage in Newborn Offspring Prenatally Exposed to Fumonisins.International journal of molecular sciences · 2021Article
- Lysosome Function in Cardiovascular Diseases.Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · 2021Review
- BMP-2 upregulates the AKT/mTOR pathway in breast cancer with microcalcification and indicates a poor prognosis.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2020Article
- Long-term use of fluoxetine accelerates bone loss through the disruption of sphingolipids metabolism in bone marrow adipose tissue.Translational psychiatry · 2020Article
- Transcriptomic landscape regulated by the 14 types of bone morphogenetic proteins (BMPs) in lineage commitment and differentiation of mesenchymal stem cells (MSCs).Genes & diseases · 2019Article
- Role of SMPD3 during Bone Fracture Healing and Regulation of Its Expression.Molecular and cellular biology · 2019Article
- Pre-transplantational Control of the Post-transplantational Fate of Human Pluripotent Stem Cell-Derived Cartilage.Stem cell reports · 2018Article
- Sphingolipids and their metabolism in physiology and disease.Nature reviews. Molecular cell biology · 2018Review
- The Expression of PHOSPHO1, nSMase2 and TNAP is Coordinately Regulated by Continuous PTH Exposure in Mineralising Osteoblast Cultures.Calcified tissue international · 2016Article
- Smpd3 Expression in both Chondrocytes and Osteoblasts Is Required for Normal Endochondral Bone Development.Molecular and cellular biology · 2016Article
- Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation.The Journal of physiology · 2016Review
- ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation.Journal of lipid research · 2016Article
- The hyaluronic acid inhibitor 4-methylumbelliferone is an NSMase2 activator-role of Ceramide in MU anti-tumor activity.Biochimica et biophysica acta · 2016Article
- Sphingolipid metabolism and its role in the skeletal tissues.Cellular and molecular life sciences : CMLS · 2015Review
- Roles and regulation of neutral sphingomyelinase-2 in cellular and pathological processes.Advances in biological regulation · 2015Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although bone morphogenic protein (BMP) signaling promotes chondrogenesis, it is not clear whether BMP-induced chondrocyte maturation is cell-autonomously terminated. Loss of function of Smpd3 in mice results in an increase in mature hypertrophic chondrocytes. Here, we report that in chondrocytes the Runx2-dependent expression of Smpd3 was increased by BMP-2 stimulation. Neutral sphingomyelinase 2 (nSMase2), encoded by the Smpd3 gene, was detected both in prehypertrophic and hypertrophic chondrocytes of mouse embryo bone cartilage. An siRNA for Smpd3, as well as the nSMase inhibitor GW4869, significantly enhanced BMP-2-induced differentiation and maturation of chondrocytes. Conversely, overexpression of Smpd3 or C2-ceramide, which mimics the function of nSMase2, inhibited chondrogenesis. Upon induction of Smpd3 siRNA or GW4869, phosphorylation of both Akt and S6 proteins was increased. The accelerated chondrogenesis induced by Smpd3 silencing was negated by application of the Akt inhibitor MK2206 or the mammalian target of rapamycin inhibitor rapamycin. Importantly, in mouse bone culture, GW4869 treatment significantly promoted BMP-2-induced hypertrophic maturation and calcification of chondrocytes, which subsequently was eliminated by C2-ceramide. Smpd3 knockdown decreased the apoptosis of terminally matured ATDC5 chondrocytes, probably as a result of decreased ceramide production. In addition, we found that expression of hyaluronan synthase 2 (Has2) was elevated by a loss of Smpd3, which was restored by MK2206. Indeed, expression of Has2 protein decreased in nSMase2-positive hypertrophic chondrocytes in the bones of mouse embryos. Our data suggest that the Smpd3/nSMase2-ceramide-Akt signaling axis negatively regulates BMP-induced chondrocyte maturation and Has2 expression to control the rate of endochondral ossification as a negative feedback mechanism.
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