Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase
Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that durin...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/5/2463 |
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| author | Amin Cressman David Morales Zhenyang Zhang Bryan Le Jackson Foley Tracy Murray-Stewart Damian C. Genetos Fernando A. Fierro |
| author_facet | Amin Cressman David Morales Zhenyang Zhang Bryan Le Jackson Foley Tracy Murray-Stewart Damian C. Genetos Fernando A. Fierro |
| author_sort | Amin Cressman |
| collection | DOAJ |
| description | Despite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels. As a result, the intracellular spermidine to spermine ratio is significantly reduced during the early stages of osteoblastogenesis. Supplementation of cells with exogenous spermidine or spermine decreases matrix mineralization in a dose-dependent manner. Employing N-cyclohexyl-1,3-propanediamine (CDAP) to chemically inhibit spermine synthase (SMS), the enzyme catalyzing conversion of spermidine into spermine, also suppresses mineralization. Intriguingly, this reduced mineralization is rescued with DFMO, an inhibitor of the upstream polyamine enzyme ornithine decarboxylase (ODC1). Similarly, high concentrations of CDAP cause cytoplasmic vacuolization and alter mitochondrial function, which are also reversible with the addition of DFMO. Altogether, these studies suggest that excess polyamines, especially spermidine, negatively affect hydroxyapatite synthesis of primary MSCs, whereas inhibition of polyamine synthesis with DFMO rescues most, but not all of these defects. These findings are relevant for patients with Snyder–Robinson syndrome (SRS), as the presenting skeletal defects—associated with SMS deficiency—could potentially be ameliorated by treatment with DFMO. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-25T00:30:20Z |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b34c644d9c2a461d93aaee1e44b947802024-03-12T16:45:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01255246310.3390/ijms25052463Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine DecarboxylaseAmin Cressman0David Morales1Zhenyang Zhang2Bryan Le3Jackson Foley4Tracy Murray-Stewart5Damian C. Genetos6Fernando A. Fierro7Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USAInstitute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USAInstitute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USAInstitute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USASidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USADepartment of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USAInstitute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USADespite the well-known relevance of polyamines to many forms of life, little is known about how polyamines regulate osteogenesis and skeletal homeostasis. Here, we report a series of in vitro studies conducted with human-bone-marrow-derived pluripotent stromal cells (MSCs). First, we show that during osteogenic differentiation, mRNA levels of most polyamine-associated enzymes are relatively constant, except for the catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), which is strongly increased at both mRNA and protein levels. As a result, the intracellular spermidine to spermine ratio is significantly reduced during the early stages of osteoblastogenesis. Supplementation of cells with exogenous spermidine or spermine decreases matrix mineralization in a dose-dependent manner. Employing N-cyclohexyl-1,3-propanediamine (CDAP) to chemically inhibit spermine synthase (SMS), the enzyme catalyzing conversion of spermidine into spermine, also suppresses mineralization. Intriguingly, this reduced mineralization is rescued with DFMO, an inhibitor of the upstream polyamine enzyme ornithine decarboxylase (ODC1). Similarly, high concentrations of CDAP cause cytoplasmic vacuolization and alter mitochondrial function, which are also reversible with the addition of DFMO. Altogether, these studies suggest that excess polyamines, especially spermidine, negatively affect hydroxyapatite synthesis of primary MSCs, whereas inhibition of polyamine synthesis with DFMO rescues most, but not all of these defects. These findings are relevant for patients with Snyder–Robinson syndrome (SRS), as the presenting skeletal defects—associated with SMS deficiency—could potentially be ameliorated by treatment with DFMO.https://www.mdpi.com/1422-0067/25/5/2463MSCsspermine synthasepolyaminesosteogenesisSnyder–Robinson syndrome |
| spellingShingle | Amin Cressman David Morales Zhenyang Zhang Bryan Le Jackson Foley Tracy Murray-Stewart Damian C. Genetos Fernando A. Fierro Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase International Journal of Molecular Sciences MSCs spermine synthase polyamines osteogenesis Snyder–Robinson syndrome |
| title | Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase |
| title_full | Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase |
| title_fullStr | Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase |
| title_full_unstemmed | Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase |
| title_short | Effects of Spermine Synthase Deficiency in Mesenchymal Stromal Cells Are Rescued by Upstream Inhibition of Ornithine Decarboxylase |
| title_sort | effects of spermine synthase deficiency in mesenchymal stromal cells are rescued by upstream inhibition of ornithine decarboxylase |
| topic | MSCs spermine synthase polyamines osteogenesis Snyder–Robinson syndrome |
| url | https://www.mdpi.com/1422-0067/25/5/2463 |
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