MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway
Hyperglycemia is one of the possible causes for osteoporosis and bone fracture in diabetes mellitus. Here we modeled diabetes-induced osteoporosis in vitro using preosteoblastic cell line MC3T3-E1 and a diabetic mice model for in vivo studies. We found that in addition to reducing osteoblast viabili...
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| Veröffentlicht in: | International journal of clinical and experimental pathology 2014-01, Vol.7 (10), p.7249-7261 |
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| creator | You, Li Gu, Wensha Chen, Lin Pan, Ling Chen, Jinyu Peng, Yongde |
| description | Hyperglycemia is one of the possible causes for osteoporosis and bone fracture in diabetes mellitus. Here we modeled diabetes-induced osteoporosis in vitro using preosteoblastic cell line MC3T3-E1 and a diabetic mice model for in vivo studies. We found that in addition to reducing osteoblast viability and differentiation (mineralization), culture in elevated glucose down regulated microRNA-378 (miR-378) expression but ectopic miR-378 expression reversed the effects of high glucose. We identified caspase-3 (CASP3) as a target of miR-378 and showed that miR-378 repressed CASP3 mRNA and protein expression under high glucose condition. We further showed that both miR-378 expression and CASP3 silencing independently restored alkaline phosphatase (ALP) activity and the expression of osteoblastic differentiation markers Runt-related transcription factor 2 (Runx2), osteorix (Osx), collagen I (Col I), osteocalcin (OCN), and osteonectin (ON). We also found that under high glucose conditions miR-378 activated the PI3K/Akt signaling pathway and down regulated pro-apoptotic CytC, Apaf-1 and Bax proteins via the PI3K/Akt pathway. Collectively, these results suggest that miR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating the PI3K/Akt pathway. |
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Here we modeled diabetes-induced osteoporosis in vitro using preosteoblastic cell line MC3T3-E1 and a diabetic mice model for in vivo studies. We found that in addition to reducing osteoblast viability and differentiation (mineralization), culture in elevated glucose down regulated microRNA-378 (miR-378) expression but ectopic miR-378 expression reversed the effects of high glucose. We identified caspase-3 (CASP3) as a target of miR-378 and showed that miR-378 repressed CASP3 mRNA and protein expression under high glucose condition. We further showed that both miR-378 expression and CASP3 silencing independently restored alkaline phosphatase (ALP) activity and the expression of osteoblastic differentiation markers Runt-related transcription factor 2 (Runx2), osteorix (Osx), collagen I (Col I), osteocalcin (OCN), and osteonectin (ON). We also found that under high glucose conditions miR-378 activated the PI3K/Akt signaling pathway and down regulated pro-apoptotic CytC, Apaf-1 and Bax proteins via the PI3K/Akt pathway. Collectively, these results suggest that miR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating the PI3K/Akt pathway.</description><identifier>EISSN: 1936-2625</identifier><identifier>PMID: 25400823</identifier><language>eng</language><publisher>United States: e-Century Publishing Corporation</publisher><subject>3T3 Cells ; Alkaline Phosphatase - metabolism ; Animals ; Apoptosis ; Calcification, Physiologic ; Caspase 3 - genetics ; Caspase 3 - metabolism ; Cell Differentiation ; Cell Survival ; Collagen Type I - metabolism ; Core Binding Factor Alpha 1 Subunit - metabolism ; Diabetes Mellitus, Experimental - enzymology ; Diabetes Mellitus, Experimental - genetics ; Diabetes Mellitus, Experimental - pathology ; Glucose - metabolism ; Male ; Mice ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Original ; Osteoblasts - enzymology ; Osteoblasts - pathology ; Osteocalcin - metabolism ; Osteogenesis ; Phosphatidylinositol 3-Kinase - metabolism ; Proto-Oncogene Proteins c-akt - metabolism ; RNA Interference ; Signal Transduction ; Sp7 Transcription Factor ; Time Factors ; Transcription Factors - metabolism ; Transfection ; Up-Regulation</subject><ispartof>International journal of clinical and experimental pathology, 2014-01, Vol.7 (10), p.7249-7261</ispartof><rights>IJCEP Copyright © 2014 2014</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230144/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230144/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25400823$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>You, Li</creatorcontrib><creatorcontrib>Gu, Wensha</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Pan, Ling</creatorcontrib><creatorcontrib>Chen, Jinyu</creatorcontrib><creatorcontrib>Peng, Yongde</creatorcontrib><title>MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway</title><title>International journal of clinical and experimental pathology</title><addtitle>Int J Clin Exp Pathol</addtitle><description>Hyperglycemia is one of the possible causes for osteoporosis and bone fracture in diabetes mellitus. Here we modeled diabetes-induced osteoporosis in vitro using preosteoblastic cell line MC3T3-E1 and a diabetic mice model for in vivo studies. We found that in addition to reducing osteoblast viability and differentiation (mineralization), culture in elevated glucose down regulated microRNA-378 (miR-378) expression but ectopic miR-378 expression reversed the effects of high glucose. We identified caspase-3 (CASP3) as a target of miR-378 and showed that miR-378 repressed CASP3 mRNA and protein expression under high glucose condition. We further showed that both miR-378 expression and CASP3 silencing independently restored alkaline phosphatase (ALP) activity and the expression of osteoblastic differentiation markers Runt-related transcription factor 2 (Runx2), osteorix (Osx), collagen I (Col I), osteocalcin (OCN), and osteonectin (ON). We also found that under high glucose conditions miR-378 activated the PI3K/Akt signaling pathway and down regulated pro-apoptotic CytC, Apaf-1 and Bax proteins via the PI3K/Akt pathway. Collectively, these results suggest that miR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating the PI3K/Akt pathway.</description><subject>3T3 Cells</subject><subject>Alkaline Phosphatase - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Calcification, Physiologic</subject><subject>Caspase 3 - genetics</subject><subject>Caspase 3 - metabolism</subject><subject>Cell Differentiation</subject><subject>Cell Survival</subject><subject>Collagen Type I - metabolism</subject><subject>Core Binding Factor Alpha 1 Subunit - metabolism</subject><subject>Diabetes Mellitus, Experimental - enzymology</subject><subject>Diabetes Mellitus, Experimental - genetics</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Glucose - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>MicroRNAs - genetics</subject><subject>MicroRNAs - metabolism</subject><subject>Original</subject><subject>Osteoblasts - enzymology</subject><subject>Osteoblasts - pathology</subject><subject>Osteocalcin - metabolism</subject><subject>Osteogenesis</subject><subject>Phosphatidylinositol 3-Kinase - metabolism</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>RNA Interference</subject><subject>Signal Transduction</subject><subject>Sp7 Transcription Factor</subject><subject>Time Factors</subject><subject>Transcription Factors - metabolism</subject><subject>Transfection</subject><subject>Up-Regulation</subject><issn>1936-2625</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUclOwzAQjZAQLYVfQD5yiXBsxykXpKpiqSiiYjlHE2eSGFI7xE6hP8L3kpaC4DTSm7fozewFw-icy5BJFg-CQ-deKJURE_QgGLBYUDpmfBh83umHkCdjYlfY4kfTonPaGgLeo-nAoyOVLitS1p2yDkPXNVsO5sQ6j7ZEoxXJdVH0cuM1-I3aV63tepWHtkSvTUmmk8cFJ2ByAsrrFWzBxYzfnk1ePXG6NFBvoAZ89Q7ro2C_gNrh8W6Oguery6fpTTi_v55NJ_OwYVL6kHMFRQJynCvJIQMGQiQsUyjzMTBeUMykivsD9DhQGReMUSpikUMmIIkYHwUX375Nly0xV32FFuq0afUS2nVqQaf_N0ZXaWlXqWCcRkL0Bqc7g9a-deh8utROYV2DQdu5NJIsoYlM-IZ68jfrN-TnGfwL5rGJlA</recordid><startdate>20140101</startdate><enddate>20140101</enddate><creator>You, Li</creator><creator>Gu, Wensha</creator><creator>Chen, Lin</creator><creator>Pan, Ling</creator><creator>Chen, Jinyu</creator><creator>Peng, Yongde</creator><general>e-Century Publishing Corporation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140101</creationdate><title>MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway</title><author>You, Li ; Gu, Wensha ; Chen, Lin ; Pan, Ling ; Chen, Jinyu ; Peng, Yongde</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p266t-33caf7a68dc63aba2a4472bce6d8a23f0eb6c5625a44a065f2200454dab4a7123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>3T3 Cells</topic><topic>Alkaline Phosphatase - metabolism</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Calcification, Physiologic</topic><topic>Caspase 3 - genetics</topic><topic>Caspase 3 - metabolism</topic><topic>Cell Differentiation</topic><topic>Cell Survival</topic><topic>Collagen Type I - metabolism</topic><topic>Core Binding Factor Alpha 1 Subunit - metabolism</topic><topic>Diabetes Mellitus, Experimental - enzymology</topic><topic>Diabetes Mellitus, Experimental - genetics</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Glucose - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>MicroRNAs - genetics</topic><topic>MicroRNAs - metabolism</topic><topic>Original</topic><topic>Osteoblasts - enzymology</topic><topic>Osteoblasts - pathology</topic><topic>Osteocalcin - metabolism</topic><topic>Osteogenesis</topic><topic>Phosphatidylinositol 3-Kinase - metabolism</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>RNA Interference</topic><topic>Signal Transduction</topic><topic>Sp7 Transcription Factor</topic><topic>Time Factors</topic><topic>Transcription Factors - metabolism</topic><topic>Transfection</topic><topic>Up-Regulation</topic><toplevel>online_resources</toplevel><creatorcontrib>You, Li</creatorcontrib><creatorcontrib>Gu, Wensha</creatorcontrib><creatorcontrib>Chen, Lin</creatorcontrib><creatorcontrib>Pan, Ling</creatorcontrib><creatorcontrib>Chen, Jinyu</creatorcontrib><creatorcontrib>Peng, Yongde</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of clinical and experimental pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>You, Li</au><au>Gu, Wensha</au><au>Chen, Lin</au><au>Pan, Ling</au><au>Chen, Jinyu</au><au>Peng, Yongde</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway</atitle><jtitle>International journal of clinical and experimental pathology</jtitle><addtitle>Int J Clin Exp Pathol</addtitle><date>2014-01-01</date><risdate>2014</risdate><volume>7</volume><issue>10</issue><spage>7249</spage><epage>7261</epage><pages>7249-7261</pages><eissn>1936-2625</eissn><abstract>Hyperglycemia is one of the possible causes for osteoporosis and bone fracture in diabetes mellitus. Here we modeled diabetes-induced osteoporosis in vitro using preosteoblastic cell line MC3T3-E1 and a diabetic mice model for in vivo studies. We found that in addition to reducing osteoblast viability and differentiation (mineralization), culture in elevated glucose down regulated microRNA-378 (miR-378) expression but ectopic miR-378 expression reversed the effects of high glucose. We identified caspase-3 (CASP3) as a target of miR-378 and showed that miR-378 repressed CASP3 mRNA and protein expression under high glucose condition. We further showed that both miR-378 expression and CASP3 silencing independently restored alkaline phosphatase (ALP) activity and the expression of osteoblastic differentiation markers Runt-related transcription factor 2 (Runx2), osteorix (Osx), collagen I (Col I), osteocalcin (OCN), and osteonectin (ON). We also found that under high glucose conditions miR-378 activated the PI3K/Akt signaling pathway and down regulated pro-apoptotic CytC, Apaf-1 and Bax proteins via the PI3K/Akt pathway. Collectively, these results suggest that miR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating the PI3K/Akt pathway.</abstract><cop>United States</cop><pub>e-Century Publishing Corporation</pub><pmid>25400823</pmid><tpages>13</tpages></addata></record> |
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| subjects | 3T3 Cells Alkaline Phosphatase - metabolism Animals Apoptosis Calcification, Physiologic Caspase 3 - genetics Caspase 3 - metabolism Cell Differentiation Cell Survival Collagen Type I - metabolism Core Binding Factor Alpha 1 Subunit - metabolism Diabetes Mellitus, Experimental - enzymology Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - pathology Glucose - metabolism Male Mice MicroRNAs - genetics MicroRNAs - metabolism Original Osteoblasts - enzymology Osteoblasts - pathology Osteocalcin - metabolism Osteogenesis Phosphatidylinositol 3-Kinase - metabolism Proto-Oncogene Proteins c-akt - metabolism RNA Interference Signal Transduction Sp7 Transcription Factor Time Factors Transcription Factors - metabolism Transfection Up-Regulation |
| title | MiR-378 overexpression attenuates high glucose-suppressed osteogenic differentiation through targeting CASP3 and activating PI3K/Akt signaling pathway |
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