{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:37:06Z","timestamp":1760146626321,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Osteoporosis Society (now known as the Royal Society for Osteoporosis)","award":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"],"award-info":[{"award-number":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"]}]},{"name":"EPSRC","award":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"],"award-info":[{"award-number":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"]}]},{"name":"Knowledge Transfer Account from Lovisenberg Diaconal Hospital Oslo, South-Eastern Norway Regional Health Authority (Oslo University Hospital)","award":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"],"award-info":[{"award-number":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"]}]},{"name":"European Union FP6 Project Osteogene","award":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"],"award-info":[{"award-number":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"]}]},{"name":"Netherlands Organisation for Health Research and Development supported F.R.","award":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"],"award-info":[{"award-number":["BH121971","EP\/K036939\/1","29750104","FP6\u2014502491","ZonMw VIDI 016.136.361","ZonMw VIDI 016.136.367"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study explores how select microRNAs (miRNAs) influence bone structure in humans and in transgenic mice. In trabecular bone biopsies from 84 postmenopausal women (healthy, osteopenic, and osteoporotic), we demonstrate that DLEU2 (deleted in lymphocytic leukemia 2)-encoded miR-15a-5p is strongly positively associated with bone mineral density (BMD) at different skeletal sites. In bone transcriptome analyses, miR-15a-5p levels correlated positively with the osteocyte characteristic transcripts SOST (encoding sclerostin) and MEPE (Matrix Extracellular Phosphoglycoprotein), while the related miR-15b-5p showed a negative association with BMD and osteoblast markers. The data imply that these miRNAs have opposite roles in bone remodeling with distinct actions on bone cells. Expression quantitative trait loci (eQTL) variants confirmed earlier DLEU2 associations. Furthermore, a novel variant (rs12585295) showed high localization with transcriptionally active chromatin states in osteoblast primary cell cultures. The supposition that DLEU2-encoded miRNAs have an important regulatory role in bone remodeling was further confirmed in a transgenic mice model showing that miR-15a\/16-1-deleted mice had significantly higher percentage bone volume and trabecular number than the wild type, possibly due to prenatal actions. However, the three-point mechanical break force test of mice femurs showed a positive correlation between strength and miR-15a-5p\/miR-16-5p levels, indicating differential effects on cortical and trabecular bone. Moreover, these miRNAs appear to have distinct and complex actions in mice prenatally and in adult humans, impacting BMD and microstructure by regulating bone cell transcription. However, detailed interactions between these miRNAs and their downstream mechanisms in health and disease need further clarification.<\/jats:p>","DOI":"10.3390\/ijms252312724","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T04:20:12Z","timestamp":1732681212000},"page":"12724","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The DLEU2\u2013miR-15a\u201316-1 Cluster Is a Determinant of Bone Microarchitecture and Strength in Postmenopausal Women and Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4330-5379","authenticated-orcid":false,"given":"Sjur","family":"Reppe","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry, Oslo University Hospital, 0450 Oslo, Norway"},{"name":"Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0456 Oslo, Norway"},{"name":"Department of Plastic and Reconstructive Surgery, Oslo University Hospital, 0424 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5743-4297","authenticated-orcid":false,"given":"Janne Elin","family":"Reseland","sequence":"additional","affiliation":[{"name":"Department of Biomaterials, Faculty of Dentistry, University of Oslo, 0317 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9463-3962","authenticated-orcid":false,"given":"Vid","family":"Prijatelj","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Prediger","sequence":"additional","affiliation":[{"name":"Blood Sciences, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Royal Victoria Infirmary, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7767-464X","authenticated-orcid":false,"given":"Liebert Parreiras","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Oral Research Laboratory, Faculty of Dentistry, University of Oslo, 0317 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tor Paaske","family":"Utheim","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Oslo University Hospital, 0450 Oslo, Norway"},{"name":"Department of Plastic and Reconstructive Surgery, Oslo University Hospital, 0424 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Rivadeneira","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3458-6113","authenticated-orcid":false,"given":"Kaare M.","family":"Gautvik","sequence":"additional","affiliation":[{"name":"Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0456 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4729-9340","authenticated-orcid":false,"given":"Harish Kumar","family":"Datta","sequence":"additional","affiliation":[{"name":"Blood Sciences (Pathology), James Cook University Hospital, Middlesbrough TS4 3BW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1002\/jbmr.5650090802","article-title":"The diagnosis of osteoporosis","volume":"9","author":"Kanis","year":"1994","journal-title":"J. Bone Miner. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1093\/nar\/gkz097","article-title":"An estimate of the total number of true human miRNAs","volume":"47","author":"Alles","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"D68","DOI":"10.1093\/nar\/gkt1181","article-title":"miRBase: Annotating high confidence microRNAs using deep sequencing data","volume":"42","author":"Kozomara","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1186\/s12967-016-0893-x","article-title":"Regulatory mechanisms of microRNA expression","volume":"14","author":"Gulyaeva","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"115760","DOI":"10.1016\/j.bone.2020.115760","article-title":"The role of microRNAs in bone development","volume":"143","author":"Hensley","year":"2021","journal-title":"Bone"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.biocel.2017.01.018","article-title":"MicroRNA-467g inhibits new bone regeneration by targeting Ihh\/Runx-2 signaling","volume":"85","author":"Kureel","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chen, Q., Liu, W., Sinha, K.M., Yasuda, H., and de Crombrugghe, B. (2013). Identification and characterization of microRNAs controlled by the osteoblast-specific transcription factor Osterix. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058104"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Laxman, N., Mallmin, H., Nilsson, O., and Kindmark, A. (2016). miR-203 and miR-320 regulate bone morphogenetic protein-2-induced osteoblast differentiation by targeting distal-less homeobox 5 (Dlx5). Genes, 8.","DOI":"10.3390\/genes8010004"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.bone.2017.07.021","article-title":"Deficiency of DGCR8 increases bone formation through downregulation of miR-22 expression","volume":"103","author":"Choi","year":"2017","journal-title":"Bone"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ydbio.2010.01.008","article-title":"Dicer inactivation in osteoprogenitor cells compromises fetal survival and bone formation, while excision in differentiated osteoblasts increases bone mass in the adult mouse","volume":"340","author":"Gaur","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pertusa, C., Tar\u00edn, J.J., Cano, A., Garc\u00eda-P\u00e9rez, M.\u00c1., and Mifsut, D. (2021). Serum microRNAs in osteoporotic fracture and osteoarthritis: A genetic and functional study. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-98789-w"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Gao, Y., Patil, S., and Qian, A. (2020). The role of microRNAs in bone metabolism and disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176081"},{"key":"ref_13","first-page":"4779","article-title":"miRNA-15a-5p facilitates the bone marrow stem cell apoptosis of femoral head necrosis through the Wnt\/\u03b2-catenin\/PPAR\u03b3 signaling pathway","volume":"19","author":"Zhang","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_14","first-page":"4810","article-title":"miR-15a-5p suppresses endometrial cancer cell growth via Wnt\/\u03b2-catenin signaling pathway by inhibiting WNT3A","volume":"21","author":"Wang","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.bone.2009.11.007","article-title":"Eight genes are highly associated with BMD variation in postmenopausal Caucasian women","volume":"46","author":"Reppe","year":"2010","journal-title":"Bone"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1002\/jbmr.3974","article-title":"Distinct subsets of noncoding RNAs are strongly associated with BMD and fracture, studied in weight-bearing and non\u2013weight-bearing human bone","volume":"35","author":"Gautvik","year":"2020","journal-title":"J. Bone Miner. Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hutter, K., R\u00fclicke, T., Szabo, T.G., Andersen, L., Villunger, A., and Herzog, S. (2022). The miR-15a\/16-1 and miR-15b\/16-2 clusters regulate early B cell development by limiting IL-7 receptor expression. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.967914"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"Integrative analysis of 111 reference human epigenomes","volume":"518","author":"Kundaje","year":"2015","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1002\/jbmr.396","article-title":"Molecular disease map of bone characterizing the postmenopausal osteoporosis phenotype","volume":"26","author":"Jemtland","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41413-020-0099-y","article-title":"Molecular mechanosensors in osteocytes","volume":"8","author":"Qin","year":"2020","journal-title":"Bone Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1136\/jcp.2007.048868","article-title":"The cell biology of bone metabolism","volume":"61","author":"Datta","year":"2008","journal-title":"J. Clin. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zeller, T., Wild, P., Szymczak, S., Rotival, M., Schillert, A., Castagne, R., Maouche, S., Germain, M., Lackner, K., and Rossmann, H. (2010). Genetics and beyond\u2013the transcriptome of human monocytes and disease susceptibility. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010693"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans","volume":"348","author":"Consortium","year":"2015","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"The 1000 Genomes Project Consortium, Auton, A., Brooks, L.D., Durbin, R.M., Garrison, E.P., and Kang, H.M. (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41588-018-0302-x","article-title":"An atlas of genetic influences on osteoporosis in humans and mice","volume":"51","author":"Morris","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1359\/jbmr.081108","article-title":"Hip fractures and the contribution of cortical versus trabecular bone to femoral neck strength","volume":"24","author":"Holzer","year":"2009","journal-title":"J. Bone Miner. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W148","DOI":"10.1093\/nar\/gkad283","article-title":"DIANA-microT 2023: Including predicted targets of virally encoded miRNAs","volume":"51","author":"Tastsoglou","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/cdd.2009.69","article-title":"miR-15a and miR-16-1 in cancer: Discovery, function and future perspectives","volume":"17","author":"Aqeilan","year":"2010","journal-title":"Cell Death Differ."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1038\/nm.1880","article-title":"The miR-15a\u2013miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities","volume":"14","author":"Bonci","year":"2008","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Feng, Q., Zheng, S., and Zheng, J. (2018). The emerging role of microRNAs in bone remodeling and its therapeutic implications for osteoporosis. Biosci. Rep., 38.","DOI":"10.1042\/BSR20180453"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.ymthe.2017.11.018","article-title":"Global microRNA profiling in human bone marrow skeletal\u2014Stromal or mesenchymal\u2013stem cells identified candidates for bone regeneration","volume":"26","author":"Chang","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_32","first-page":"241","article-title":"Osteoblastic microRNAs in skeletal diseases: Biological functions and therapeutic implications","volume":"3","author":"Yu","year":"2022","journal-title":"Eng. Regen."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Oka, S., Li, X., Zhang, F., Tewari, N., Ma, R., Zhong, L., Makishima, M., Liu, Y., and Bhawal, U.K. (2021). MicroRNA-21 facilitates osteoblast activity. Biochem. Biophys. Rep., 25.","DOI":"10.1016\/j.bbrep.2020.100894"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"117273","DOI":"10.1016\/j.bone.2024.117273","article-title":"microRNA-324 mediates bone homeostasis and the regulation of osteoblast and osteoclast differentiation and activity","volume":"190","author":"Hayman","year":"2025","journal-title":"Bone"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115994","DOI":"10.1016\/j.bone.2021.115994","article-title":"MicroRNAs and osteocytes","volume":"150","author":"Plotkin","year":"2021","journal-title":"Bone"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"115757","DOI":"10.1016\/j.bone.2020.115757","article-title":"miRNAs in osteoclast biology","volume":"143","author":"Weivoda","year":"2021","journal-title":"Bone"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"422","DOI":"10.2174\/1389450117666160502144329","article-title":"MicroRNAs as potential targets for treatment of osteoclast-related diseases","volume":"19","author":"Li","year":"2018","journal-title":"Curr. Drug Targets"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10872","DOI":"10.1038\/ncomms10872","article-title":"Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation","volume":"7","author":"Li","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Huai, Y., Zhang, W., Chen, Z., Zhao, F., Wang, W., Dang, K., Xue, K., Gao, Y., Jiang, S., and Miao, Z. (2020). A comprehensive analysis of MicroRNAs in human osteoporosis. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.516213"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Trojniak, J., Sendera, A., Bana\u015b-Z\u0105bczyk, A., and Kopa\u0144ska, M. (2024). The MicroRNAs in the Pathophysiology of Osteoporosis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116240"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1136\/bmj.1.5541.682-a","article-title":"Trephine for full-thickness iliac-crest biopsy","volume":"1","author":"Byers","year":"1967","journal-title":"Br. Med. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1093\/bioinformatics\/bts479","article-title":"zCall: A rare variant caller for array-based genotyping: Genetics and population analysis","volume":"28","author":"Goldstein","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1093\/bioinformatics\/btq559","article-title":"Robust relationship inference in genome-wide association studies","volume":"26","author":"Manichaikul","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nmeth.1785","article-title":"A linear complexity phasing method for thousands of genomes","volume":"9","author":"Delaneau","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Stahl, K., Gola, D., and K\u00f6nig, I.R. (2021). Assessment of imputation quality: Comparison of phasing and imputation algorithms in real data. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.724037"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1038\/ng.3643","article-title":"A reference panel of 64,976 haplotypes for genotype imputation","volume":"48","author":"Kretzschmar","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1093\/bioinformatics\/btw079","article-title":"RVTESTS: An efficient and comprehensive tool for rare variant association analysis using sequence data","volume":"32","author":"Zhan","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41584-021-00711-1","article-title":"The Musculoskeletal Knowledge Portal: Improving access to multi-omics data","volume":"18","author":"Westendorf","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1093\/bioinformatics\/btv402","article-title":"LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants","volume":"31","author":"Machiela","year":"2015","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12724\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:40:12Z","timestamp":1760114412000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12724"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":49,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252312724"],"URL":"https:\/\/doi.org\/10.3390\/ijms252312724","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,11,27]]}}}