{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:45:04Z","timestamp":1788522304590,"version":"build-2803163510"},"reference-count":24,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T00:00:00Z","timestamp":1646784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This project was supported by the National Osteoporosis Society (# BH121971), EPSRC (EP\/K036939\/1), Knowledge Transfer Account from Lovisenberg Diaconal Hospital Oslo, South-Eastern Norway Regional Health Authority (Oslo University Hospital) (Project 2975","award":["# BH121971, EP\/K036939\/1,Project 29750104,FP6 - 502491"],"award-info":[{"award-number":["# BH121971, EP\/K036939\/1,Project 29750104,FP6 - 502491"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mechanical loading exerts a profound influence on bone density and architecture, but the exact mechanism is unknown. Our study shows that expression of the neurological transcriptional factor zinc finger of the cerebellum 1 (ZIC1) is markedly increased in trabecular bone biopsies in the lumbar spine compared with the iliac crest, skeletal sites of high and low mechanical stress, respectively. Human trabecular bone transcriptome analyses revealed a strong association between ZIC1 mRNA levels and gene transcripts characteristically associated with osteoblasts, osteocytes and osteoclasts. This supposition is supported by higher ZIC1 expression in iliac bone biopsies from postmenopausal women with osteoporosis compared with age-matched control subjects, as well as strongly significant inverse correlation between ZIC1 mRNA levels and BMI-adjusted bone mineral density (BMD) (Z-score). ZIC1 promoter methylation was decreased in mechanically loaded vertebral bone compared to unloaded normal iliac bone, and its mRNA levels correlated inversely with ZIC1 promoter methylation, thus linking mechanical stress to epigenetic control of gene expression. The findings were corroborated in cultures of rat osteoblast progenitors and osteoblast-like cells. This study demonstrates for the first time how skeletal epigenetic changes that are affected by mechanical forces give rise to marked alteration in bone cell transcriptional activity and translate to human bone pathophysiology.<\/jats:p>","DOI":"10.3390\/ijms23062957","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T11:30:38Z","timestamp":1646825438000},"page":"2957","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Mechanical-Stress-Related Epigenetic Regulation of ZIC1 Transcription Factor in the Etiology of Postmenopausal Osteoporosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4729-9340","authenticated-orcid":false,"given":"Harish K.","family":"Datta","sequence":"first","affiliation":[{"name":"Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Blood Sciences, South Tees Hospitals NHS Foundation Trust, Middlesbrough TS4 3BW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne K.","family":"Kringen","sequence":"additional","affiliation":[{"name":"Center for Psychopharmacology, Diakonhjemmet Hospital, 0319 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5060-4214","authenticated-orcid":false,"given":"Stephen P.","family":"Tuck","sequence":"additional","affiliation":[{"name":"Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Salpingidou","sequence":"additional","affiliation":[{"name":"Department of Engineering, Faculty of Science, Durham University, Durham DH1 3 LE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole K.","family":"Olstad","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaare M.","family":"Gautvik","sequence":"additional","affiliation":[{"name":"Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0440 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6831-9806","authenticated-orcid":false,"given":"Simon J.","family":"Cockell","sequence":"additional","affiliation":[{"name":"School of Biomedical, Nutritional and Sport Sciences, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vigdis T.","family":"Gautvik","sequence":"additional","affiliation":[{"name":"Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0440 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Jie","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Engineering, Faculty of Science, Durham University, Durham DH1 3 LE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Birch","sequence":"additional","affiliation":[{"name":"Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4330-5379","authenticated-orcid":false,"given":"Sjur","family":"Reppe","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Oslo University Hospital, 0424 Oslo, Norway"},{"name":"Unger-Vetlesen Institute, Lovisenberg Diaconal Hospital, 0440 Oslo, Norway"},{"name":"Department of Plastic and Reconstructive Surgery, Oslo University Hospital, 0424 Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1096\/fj.09-148908","article-title":"Zic1 transcription factor in bone: Neural developmental protein regulates mechanotransduction in osteocytes","volume":"24","author":"Kalogeropoulos","year":"2010","journal-title":"FASEB J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Varanasi, S.S., Olstad, O.K., Swan, D.C., Sanderson, P., Gautvik, V.T., Reppe, S., Francis, R.M., Gautvik, K.M., and Datta, H.K. (2010). Skeletal site-related variation in human trabecular bone transcriptome and signaling. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010692"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mansour, T.A., Lucot, K., Konopelski, S.E., Dickinson, P.J., Sturges, B.K., Vernau, K.L., Choi, S., Stern, J.A., Thomasy, S.M., and D\u00f6ring, S. (2018). Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007850"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Medina-Gomez, C., Mullin, B.H., Chesi, A., Prijatelj, V., Kemp, J.P., Shochat-Carvalho, C., Trajanoska, K., Wang, C., Joro, R., and Evans, T.E. (2021). Genome Wide Association Metanalysis of Skull Bone Mineral Density Identifies Loci Relevant for Osteoporosis and Craniosynostosis. medRxiv.","DOI":"10.1101\/2021.11.01.21265592"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/jbmr.320","article-title":"The amazing osteocyte","volume":"26","author":"Bonewald","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_6","first-page":"239","article-title":"Osteocytes: A proposed multifunctional bone cell","volume":"2","author":"Bonewald","year":"2002","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1210\/er.2012-1026","article-title":"The osteocyte: An endocrine cell\u2026 and more","volume":"34","author":"Dallas","year":"2013","journal-title":"Endocr. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1177\/1759720X09341484","article-title":"Advancing our understanding of osteocyte cell biology","volume":"1","author":"Guo","year":"2009","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/BF02408535","article-title":"Electrical potential difference across bone membrane","volume":"32","author":"Trumbore","year":"1980","journal-title":"Calcif. Tissue Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.bone.2007.12.224","article-title":"Osteocytes, mechanosensing and Wnt signaling","volume":"42","author":"Bonewald","year":"2008","journal-title":"Bone"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13648","DOI":"10.1073\/pnas.1009382107","article-title":"Dendritic processes of osteocytes are mechanotransducers that induce the opening of hemichannels","volume":"107","author":"Burra","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1007\/s11914-011-0078-8","article-title":"Bone development: Overview of bone cells and signaling","volume":"9","author":"Teti","year":"2011","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zhong, J., Chen, S., Xue, M., Du, Q., Cai, J., Jin, H., Si, J., and Wang, L. (2012). ZIC1 modulates cell-cycle distributions and cell migration through regulation of sonic hedgehog, PI 3 K and MAPK signaling pathways in gastric cancer. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-290"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1387\/ijdb.052110cm","article-title":"The zic1 gene is an activator of Wnt signaling","volume":"50","author":"Merzdorf","year":"2004","journal-title":"Int. J. Dev. Biol."},{"key":"ref_16","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_17","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_18","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1146\/annurev-bioeng-070909-105302","article-title":"Osteocyte mechanobiology and pericellular mechanics","volume":"12","author":"Jacobs","year":"2010","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature10316","article-title":"Dynamic molecular processes mediate cellular mechanotransduction","volume":"475","author":"Hoffman","year":"2011","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.bone.2010.02.006","article-title":"Effects of cyclic hydraulic pressure on osteocytes","volume":"46","author":"Liu","year":"2010","journal-title":"Bone"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1080\/15592294.2017.1345832","article-title":"Distinct DNA methylation profiles in bone and blood of osteoporotic and healthy postmenopausal women","volume":"12","author":"Reppe","year":"2017","journal-title":"Epigenetics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: A flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1093\/bioinformatics\/bts680","article-title":"A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data","volume":"29","author":"Teschendorff","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1089\/ten.tea.2008.0137","article-title":"Microfabricated grooved substrates influence cell\u2013cell communication and osteoblast differentiation in vitro","volume":"15","author":"Kirmizidis","year":"2008","journal-title":"Tissue Eng. 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