SNPs in bone-related miRNAs are associated with the osteoporotic phenotype

Abstract Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering a...

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Main Authors: Laura De-Ugarte, Enrique Caro-Molina, Maria Rodríguez-Sanz, Miguel Angel García-Pérez, José M. Olmos, Manuel Sosa-Henríquez, Ramón Pérez-Cano, Carlos Gómez-Alonso, Luis Del Rio, Jesús Mateo-Agudo, José Antonio Blázquez-Cabrera, Jesús González-Macías, Javier del Pino-Montes, Manuel Muñoz-Torres, Manuel Diaz-Curiel, Jorge Malouf, Antonio Cano, José Luis Pérez-Castrillon, Xavier Nogues, Natalia Garcia-Giralt, Adolfo Diez-Perez
Format: Article
Language:English
Published: Nature Portfolio 2017-03-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-017-00641-7
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author Laura De-Ugarte
Enrique Caro-Molina
Maria Rodríguez-Sanz
Miguel Angel García-Pérez
José M. Olmos
Manuel Sosa-Henríquez
Ramón Pérez-Cano
Carlos Gómez-Alonso
Luis Del Rio
Jesús Mateo-Agudo
José Antonio Blázquez-Cabrera
Jesús González-Macías
Javier del Pino-Montes
Manuel Muñoz-Torres
Manuel Diaz-Curiel
Jorge Malouf
Antonio Cano
José Luis Pérez-Castrillon
Xavier Nogues
Natalia Garcia-Giralt
Adolfo Diez-Perez
author_facet Laura De-Ugarte
Enrique Caro-Molina
Maria Rodríguez-Sanz
Miguel Angel García-Pérez
José M. Olmos
Manuel Sosa-Henríquez
Ramón Pérez-Cano
Carlos Gómez-Alonso
Luis Del Rio
Jesús Mateo-Agudo
José Antonio Blázquez-Cabrera
Jesús González-Macías
Javier del Pino-Montes
Manuel Muñoz-Torres
Manuel Diaz-Curiel
Jorge Malouf
Antonio Cano
José Luis Pérez-Castrillon
Xavier Nogues
Natalia Garcia-Giralt
Adolfo Diez-Perez
author_sort Laura De-Ugarte
collection DOAJ
description Abstract Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.
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spelling doaj.art-b02685a070da4fae9bc27bc45550d8512022-12-21T20:34:53ZengNature PortfolioScientific Reports2045-23222017-03-017111010.1038/s41598-017-00641-7SNPs in bone-related miRNAs are associated with the osteoporotic phenotypeLaura De-Ugarte0Enrique Caro-Molina1Maria Rodríguez-Sanz2Miguel Angel García-Pérez3José M. Olmos4Manuel Sosa-Henríquez5Ramón Pérez-Cano6Carlos Gómez-Alonso7Luis Del Rio8Jesús Mateo-Agudo9José Antonio Blázquez-Cabrera10Jesús González-Macías11Javier del Pino-Montes12Manuel Muñoz-Torres13Manuel Diaz-Curiel14Jorge Malouf15Antonio Cano16José Luis Pérez-Castrillon17Xavier Nogues18Natalia Garcia-Giralt19Adolfo Diez-Perez20IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII)IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII)IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII)Department of Genetics and Institute of Health Research INCLIVA, University of ValenciaDepartment of Internal Medicine, Hospital Universitario Marqués de Valdecilla-IDIVAL/Hospital de Torrelavega, Universidad de Cantabria. RETICEFUnidad Metabólica Ósea, Hospital Universitario Insular, Universidad de Las Palmas de Gran CanariaDepartamento de Medicina (USE), UGC Medicina Interna, Hospital Universitario Virgen MacarenaServicio de Metabolismo Óseo y Mineral, Hospital Universitario Central de AsturiasCETIR Grup Mèdic, RETICEFServicio COT, Hospital Universitario Miguel ServetServicio de Medicina Interna, Complejo Hospitalario Universitario de AlbaceteDepartamento de Medicina Interna, H. Marqués de Valdecilla, Universidad de Cantabria, IDIVAL, RETICEFServicio de Reumatología. Hospital Universitario de Salamanca, RETICEF (ISCIII), IBSAL (Biomedical Research Institute of Salamanca)UGC Endocrinologia y Nutrición. Hospital Universitario San Cecilio. Granada, RETICEF, IbsUnidad de Enfermedades Metabólicas Óseas. Servicio de Medicina Interna. Fundacion Jimenez DiazHospital de la Santa Creu I Sant Pau. Institut d’Investigació Biomèdica Sant PauDepartment of Pediatrics, Obstetrics and Gynecology, University of Valencia, INCLIVAHospital Universitario Río HortegaIMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII)IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII)IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, CIBERFES, RETICEF (ISCIII)Abstract Biogenesis and function of microRNAs can be influenced by genetic variants in the pri-miRNA sequences leading to phenotypic variability. This study aims to identify single nucleotide polymorphisms (SNPs) affecting the expression levels of bone-related mature microRNAs and thus, triggering an osteoporotic phenotype. An association analysis of SNPs located in pri-miRNA sequences with bone mineral density (BMD) was performed in the OSTEOMED2 cohort (n = 2183). Functional studies were performed for assessing the role of BMD-associated miRNAs in bone cells. Two SNPs, rs6430498 in the miR-3679 and rs12512664 in the miR-4274, were significantly associated with femoral neck BMD. Further, we measured these BMD-associated microRNAs in trabecular bone from osteoporotic hip fractures comparing to non-osteoporotic bone by qPCR. Both microRNAs were found overexpressed in fractured bone. Increased matrix mineralization was observed after miR-3679-3p inhibition in human osteoblastic cells. Finally, genotypes of rs6430498 and rs12512664 were correlated with expression levels of miR-3679 and miR-4274, respectively, in osteoblasts. In both cases, the allele that generated higher microRNA expression levels was associated with lower BMD values. In conclusion, two osteoblast-expressed microRNAs, miR-3679 and miR-4274, were associated with BMD; their overexpression could contribute to the osteoporotic phenotype. These findings open new areas for the study of bone disorders.https://doi.org/10.1038/s41598-017-00641-7
spellingShingle Laura De-Ugarte
Enrique Caro-Molina
Maria Rodríguez-Sanz
Miguel Angel García-Pérez
José M. Olmos
Manuel Sosa-Henríquez
Ramón Pérez-Cano
Carlos Gómez-Alonso
Luis Del Rio
Jesús Mateo-Agudo
José Antonio Blázquez-Cabrera
Jesús González-Macías
Javier del Pino-Montes
Manuel Muñoz-Torres
Manuel Diaz-Curiel
Jorge Malouf
Antonio Cano
José Luis Pérez-Castrillon
Xavier Nogues
Natalia Garcia-Giralt
Adolfo Diez-Perez
SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
Scientific Reports
title SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
title_full SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
title_fullStr SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
title_full_unstemmed SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
title_short SNPs in bone-related miRNAs are associated with the osteoporotic phenotype
title_sort snps in bone related mirnas are associated with the osteoporotic phenotype
url https://doi.org/10.1038/s41598-017-00641-7
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