Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites
1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) had earlier been regarded as the only active hormone. The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a syst...
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| description | 1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) had earlier been regarded as the only active hormone. The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D3 into 1α,25(OH)2D3 by 1α-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1α,25(OH)2D3, 25(OH)D3, and 24R,25(OH)2D3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1 (-/-)), which lack 1α-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1 (-/-). By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D3 endocrine system, which may guide the strategic use of vitamin D3 in disease prevention and treatment. |
| doi_str_mv | 10.1371/journal.pone.0075338 |
| format | Article |
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The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D3 into 1α,25(OH)2D3 by 1α-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1α,25(OH)2D3, 25(OH)D3, and 24R,25(OH)2D3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1 (-/-)), which lack 1α-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1 (-/-). By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D3 endocrine system, which may guide the strategic use of vitamin D3 in disease prevention and treatment.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0075338</identifier><identifier>PMID: 24116037</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amyotrophic lateral sclerosis ; Animals ; Annotations ; Bioinformatics ; Biotechnology ; Bone remodeling ; Calcifediol - pharmacology ; Calcitriol - pharmacology ; Calcium ; Calcium homeostasis ; Cancer ; Cell cycle ; Cell Cycle - drug effects ; Cell death ; Cell differentiation ; Cell Differentiation - drug effects ; Cell growth ; Cholecalciferol - metabolism ; Cholecalciferol - pharmacology ; Deoxyribonucleic acid ; Differentiation (biology) ; Dihydroxyvitamin D3 ; DNA ; DNA microarrays ; Endocrine system ; Epigenetics ; Ethanol ; Experiments ; Fibroblasts ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Gene expression ; Gene Expression - drug effects ; Gene Expression Profiling ; Genes ; Homeostasis ; Hormones ; Humans ; Hydroxylase ; Hydroxylation ; Immunomodulation ; Kinases ; Laboratory animals ; Leukemia ; Medical schools ; Medical treatment ; Membrane proteins ; Metabolites ; Mice ; Mice, Knockout ; Prostate ; Proteins ; Signal transduction ; Stromal Cells - drug effects ; Stromal Cells - metabolism ; Transcription ; Vitamin D3</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e75338</ispartof><rights>2013 Tuohimaa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Tuohimaa et al 2013 Tuohimaa et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4418-553fd49d98e4605e0270fbee41d8adc66409a2de42ff7a78e50ebfee6fe63f343</citedby><cites>FETCH-LOGICAL-c4418-553fd49d98e4605e0270fbee41d8adc66409a2de42ff7a78e50ebfee6fe63f343</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792969/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792969/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24116037$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Slominski, Andrzej T.</contributor><creatorcontrib>Tuohimaa, Pentti</creatorcontrib><creatorcontrib>Wang, Jing-Huan</creatorcontrib><creatorcontrib>Khan, Sofia</creatorcontrib><creatorcontrib>Kuuslahti, Marianne</creatorcontrib><creatorcontrib>Qian, Kui</creatorcontrib><creatorcontrib>Manninen, Tommi</creatorcontrib><creatorcontrib>Auvinen, Petri</creatorcontrib><creatorcontrib>Vihinen, Mauno</creatorcontrib><creatorcontrib>Lou, Yan-Ru</creatorcontrib><title>Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3) had earlier been regarded as the only active hormone. The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D3 into 1α,25(OH)2D3 by 1α-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1α,25(OH)2D3, 25(OH)D3, and 24R,25(OH)2D3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1 (-/-)), which lack 1α-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1 (-/-). By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D3 endocrine system, which may guide the strategic use of vitamin D3 in disease prevention and treatment.</description><subject>Amyotrophic lateral sclerosis</subject><subject>Animals</subject><subject>Annotations</subject><subject>Bioinformatics</subject><subject>Biotechnology</subject><subject>Bone remodeling</subject><subject>Calcifediol - pharmacology</subject><subject>Calcitriol - pharmacology</subject><subject>Calcium</subject><subject>Calcium homeostasis</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell death</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell growth</subject><subject>Cholecalciferol - metabolism</subject><subject>Cholecalciferol - pharmacology</subject><subject>Deoxyribonucleic acid</subject><subject>Differentiation (biology)</subject><subject>Dihydroxyvitamin D3</subject><subject>DNA</subject><subject>DNA microarrays</subject><subject>Endocrine system</subject><subject>Epigenetics</subject><subject>Ethanol</subject><subject>Experiments</subject><subject>Fibroblasts</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression - drug effects</subject><subject>Gene Expression Profiling</subject><subject>Genes</subject><subject>Homeostasis</subject><subject>Hormones</subject><subject>Humans</subject><subject>Hydroxylase</subject><subject>Hydroxylation</subject><subject>Immunomodulation</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Leukemia</subject><subject>Medical schools</subject><subject>Medical treatment</subject><subject>Membrane proteins</subject><subject>Metabolites</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Prostate</subject><subject>Proteins</subject><subject>Signal transduction</subject><subject>Stromal Cells - drug effects</subject><subject>Stromal Cells - metabolism</subject><subject>Transcription</subject><subject>Vitamin D3</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp1Ustu1DAUtRCIloE_QGCJ9Qx-xUk2SKhAqVSJDawtJ76e8cixB9uZwg_0u5swadUuWNnyPY_ro4PQW0o2lNf04z6OKWi_OcQAG0LqivPmGTqnLWdryQh__uh-hl7lvCek4o2UL9EZE5RKwutzdHsJATD8OSTI2cWADyla5yFjF_BuHHTAOhg8xDHDNHODTn9xD97nGXl0BnCAmwmc3XZXZlaJuOwAG2ctJAjFaY91XybtjKPFR1f0MGl_4XiAorvoXYH8Gr2w2md4s5wr9Ovb158X39fXPy6vLj5fr3shaLOuKm6NaE3bgJCkAsJqYjsAQU2jTS-lIK1mBgSzttZ1AxWBzgJIC5JbLvgKvT_pHnzMaokwKyoE4ZTTKcQVujohTNR7tfxYRe3Uv4eYtkqn4noPqmOGycaAZFUroKEt1MIwrknXc9J3s9unxW3sBjD9lEbS_ono00lwO7WNR8XrlrWynQQ-LAIp_h4hl_-sLE6oPsWcE9gHB0rU3JV7lpq7opauTLR3j7d7IN2Xg98BmObAtw</recordid><startdate>20131008</startdate><enddate>20131008</enddate><creator>Tuohimaa, Pentti</creator><creator>Wang, Jing-Huan</creator><creator>Khan, Sofia</creator><creator>Kuuslahti, Marianne</creator><creator>Qian, Kui</creator><creator>Manninen, Tommi</creator><creator>Auvinen, Petri</creator><creator>Vihinen, Mauno</creator><creator>Lou, Yan-Ru</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131008</creationdate><title>Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites</title><author>Tuohimaa, Pentti ; Wang, Jing-Huan ; Khan, Sofia ; Kuuslahti, Marianne ; Qian, Kui ; Manninen, Tommi ; Auvinen, Petri ; Vihinen, Mauno ; Lou, Yan-Ru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4418-553fd49d98e4605e0270fbee41d8adc66409a2de42ff7a78e50ebfee6fe63f343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amyotrophic lateral sclerosis</topic><topic>Animals</topic><topic>Annotations</topic><topic>Bioinformatics</topic><topic>Biotechnology</topic><topic>Bone remodeling</topic><topic>Calcifediol - pharmacology</topic><topic>Calcitriol - pharmacology</topic><topic>Calcium</topic><topic>Calcium homeostasis</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Cell Cycle - drug effects</topic><topic>Cell death</topic><topic>Cell differentiation</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell growth</topic><topic>Cholecalciferol - metabolism</topic><topic>Cholecalciferol - pharmacology</topic><topic>Deoxyribonucleic acid</topic><topic>Differentiation (biology)</topic><topic>Dihydroxyvitamin D3</topic><topic>DNA</topic><topic>DNA microarrays</topic><topic>Endocrine system</topic><topic>Epigenetics</topic><topic>Ethanol</topic><topic>Experiments</topic><topic>Fibroblasts</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression - drug effects</topic><topic>Gene Expression Profiling</topic><topic>Genes</topic><topic>Homeostasis</topic><topic>Hormones</topic><topic>Humans</topic><topic>Hydroxylase</topic><topic>Hydroxylation</topic><topic>Immunomodulation</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Leukemia</topic><topic>Medical schools</topic><topic>Medical treatment</topic><topic>Membrane proteins</topic><topic>Metabolites</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Prostate</topic><topic>Proteins</topic><topic>Signal transduction</topic><topic>Stromal Cells - 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The newly identified actions of 25-hydroxyvitamin D3 (25(OH)D3) and 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) broadened the vitamin D3 endocrine system, however, the current data are fragmented and a systematic understanding is lacking. Here we performed the first systematic study of global gene expression to clarify their similarities and differences. Three metabolites at physiologically comparable levels were utilized to treat human and mouse fibroblasts prior to DNA microarray analyses. Human primary prostate stromal P29SN cells (hP29SN), which convert 25(OH)D3 into 1α,25(OH)2D3 by 1α-hydroxylase (encoded by the gene CYP27B1), displayed regulation of 164, 171, and 175 genes by treatment with 1α,25(OH)2D3, 25(OH)D3, and 24R,25(OH)2D3, respectively. Mouse primary Cyp27b1 knockout fibroblasts (mCyp27b1 (-/-)), which lack 1α-hydroxylation, displayed regulation of 619, 469, and 66 genes using the same respective treatments. The number of shared genes regulated by two metabolites is much lower in hP29SN than in mCyp27b1 (-/-). By using DAVID Functional Annotation Bioinformatics Microarray Analysis tools and Ingenuity Pathways Analysis, we identified the agonistic regulation of calcium homeostasis and bone remodeling between 1α,25(OH)2D3 and 25(OH)D3 and unique non-classical actions of each metabolite in physiological and pathological processes, including cell cycle, keratinocyte differentiation, amyotrophic lateral sclerosis signaling, gene transcription, immunomodulation, epigenetics, cell differentiation, and membrane protein expression. In conclusion, there are three distinct vitamin D3 hormones with clearly different biological activities. This study presents a new conceptual insight into the vitamin D3 endocrine system, which may guide the strategic use of vitamin D3 in disease prevention and treatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24116037</pmid><doi>10.1371/journal.pone.0075338</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1440313175 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Amyotrophic lateral sclerosis Animals Annotations Bioinformatics Biotechnology Bone remodeling Calcifediol - pharmacology Calcitriol - pharmacology Calcium Calcium homeostasis Cancer Cell cycle Cell Cycle - drug effects Cell death Cell differentiation Cell Differentiation - drug effects Cell growth Cholecalciferol - metabolism Cholecalciferol - pharmacology Deoxyribonucleic acid Differentiation (biology) Dihydroxyvitamin D3 DNA DNA microarrays Endocrine system Epigenetics Ethanol Experiments Fibroblasts Fibroblasts - drug effects Fibroblasts - metabolism Gene expression Gene Expression - drug effects Gene Expression Profiling Genes Homeostasis Hormones Humans Hydroxylase Hydroxylation Immunomodulation Kinases Laboratory animals Leukemia Medical schools Medical treatment Membrane proteins Metabolites Mice Mice, Knockout Prostate Proteins Signal transduction Stromal Cells - drug effects Stromal Cells - metabolism Transcription Vitamin D3 |
| title | Gene expression profiles in human and mouse primary cells provide new insights into the differential actions of vitamin D3 metabolites |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T20%3A52%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Gene%20expression%20profiles%20in%20human%20and%20mouse%20primary%20cells%20provide%20new%20insights%20into%20the%20differential%20actions%20of%20vitamin%20D3%20metabolites&rft.jtitle=PloS%20one&rft.au=Tuohimaa,%20Pentti&rft.date=2013-10-08&rft.volume=8&rft.issue=10&rft.spage=e75338&rft.pages=e75338-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0075338&rft_dat=%3Cproquest_plos_%3E3093582291%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1440313175&rft_id=info:pmid/24116037&rft_doaj_id=oai_doaj_org_article_b2d268de62594e819e74d23a0bc30cb4&rfr_iscdi=true |