{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:55:16Z","timestamp":1785243316573,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Defects in the extracellular matrix protein fibrillin-1 that perturb transforming growth factor beta (TGF\u03b2) bioavailability lead to Marfan syndrome (MFS). MFS is an autosomal-dominant disorder, which is associated with connective tissue and skeletal defects, among others. To date, it is unclear how biological sex impacts the structural and functional properties of bone in MFS. The aim of this study was to investigate the effects of sex on bone microarchitecture and mechanical properties in mice with deficient fibrillin-1, a model of human MFS. Bones of 11-week-old male and female Fbn1mgR\/mgR mice were investigated. Three-dimensional micro-computed tomography of femora and vertebrae revealed a lower ratio of trabecular bone volume to tissue volume, reduced trabecular number and thickness, and greater trabecular separation in females vs. males. Three-point bending of femora revealed significantly lower post-yield displacement and work-to-fracture in females vs. males. Mechanistically, we found higher Smad2 and ERK1\/2 phosphorylation in females vs. males, demonstrating a greater activation of TGF\u03b2 signaling in females. In summary, the present findings show pronounced sex differences in the matrix and function of bones deficient in fibrillin-1 microfibrils. Consequently, sex-specific analysis of bone characteristics in patients with MFS may prove useful in improving the clinical management and life quality of these patients, through the development of sex-specific therapeutic approaches.<\/jats:p>","DOI":"10.3390\/ijms20236059","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T10:50:45Z","timestamp":1575283845000},"page":"6059","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0904-7003","authenticated-orcid":false,"given":"Lukas","family":"Altinbas","sequence":"first","affiliation":[{"name":"BIH Center for Regenerative Therapies, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Bormann","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lehmann","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3811-6327","authenticated-orcid":false,"given":"Sarah","family":"Jeuthe","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dag","family":"Wulsten","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Kornak","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Institute for Medical Genetics and Human Genetics, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0736-9199","authenticated-orcid":false,"given":"Peter N.","family":"Robinson","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-1188","authenticated-orcid":false,"given":"Britt","family":"Wildemann","sequence":"additional","affiliation":[{"name":"BIH Center for Regenerative Therapies, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Experimental Trauma Surgery, University Hospital Jena, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8187-0176","authenticated-orcid":false,"given":"Georgios","family":"Kararigas","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s00441-009-0822-x","article-title":"Biogenesis and function of fibrillin assemblies","volume":"339","author":"Ramirez","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.matbio.2017.07.004","article-title":"Marfan syndrome; A connective tissue disease at the crossroads of mechanotransduction, TGFbeta signaling and cell stemness","volume":"71","author":"Ramirez","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1016\/S0140-6736(05)67789-6","article-title":"Marfan\u2019s syndrome","volume":"366","author":"Judge","year":"2005","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/03008200701820708","article-title":"Fibrillin-rich microfibrils-structural and instructive determinants of mammalian development and physiology","volume":"49","author":"Ramirez","year":"2008","journal-title":"Connect. Tissue Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.matbio.2015.09.004","article-title":"Fibrillin microfibrils in bone physiology","volume":"52","author":"Smaldone","year":"2016","journal-title":"Matrix Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/0002-9343(93)90351-O","article-title":"Bone mineral status of women with Marfan syndrome","volume":"95","author":"Kohlmeier","year":"1993","journal-title":"Am. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.jbspin.2006.01.026","article-title":"Bone mineral density in Marfan syndrome. A large case-control study","volume":"73","author":"Moura","year":"2006","journal-title":"Jt. Bone Spine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/rheumatology\/39.3.307","article-title":"Bone mineral density in adults with Marfan syndrome","volume":"39","author":"Carter","year":"2000","journal-title":"Rheumatology (Oxf.)"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1002\/jbmr.5650101017","article-title":"The bone mineral status of patients with Marfan syndrome","volume":"10","author":"Kohlmeier","year":"1995","journal-title":"J. Bone Min. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1002\/jbmr.2471","article-title":"Muscle and Bone Impairment in Children With Marfan Syndrome: Correlation With Age and FBN1 Genotype","volume":"30","author":"Haine","year":"2015","journal-title":"J. Bone Min. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1002\/ajmg.a.35540","article-title":"Assessment of bone mineral status in children with Marfan syndrome","volume":"158","author":"Grover","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.bone.2014.12.006","article-title":"Areal bone mineral density in children and adolescents with Marfan syndrome: Evidence of an evolving problem","volume":"73","author":"Trifiro","year":"2015","journal-title":"Bone"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physrev.00021.2015","article-title":"Mechanistic Pathways of Sex Differences in Cardiovascular Disease","volume":"97","author":"Kararigas","year":"2017","journal-title":"Physiol. Rev."},{"key":"ref_14","first-page":"149","article-title":"Why the study of the effects of biological sex is important. Commentary","volume":"52","author":"Kararigas","year":"2016","journal-title":"Ann. Ist. Super Sanita"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1136\/pgmj.69.811.373","article-title":"Osteoporosis and the Marfan syndrome","volume":"69","author":"Gray","year":"1993","journal-title":"Postgrad. Med. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3819","DOI":"10.1073\/pnas.96.7.3819","article-title":"Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1","volume":"96","author":"Pereira","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4790","DOI":"10.1093\/hmg\/ddq409","article-title":"Differential effects of alendronate and losartan therapy on osteopenia and aortic aneurysm in mice with severe Marfan syndrome","volume":"19","author":"Nistala","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1359\/jbmr.070507","article-title":"Age-related changes in trabecular architecture differ in female and male C57BL\/6J mice","volume":"22","author":"Glatt","year":"2007","journal-title":"J. Bone Min. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/ng1116","article-title":"Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome","volume":"33","author":"Neptune","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1083\/jcb.200608167","article-title":"Fibrillin-1 regulates the bioavailability of TGFbeta1","volume":"176","author":"Chaudhry","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-beta family signalling","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1126\/science.1192149","article-title":"Noncanonical TGFbeta signaling contributes to aortic aneurysm progression in Marfan syndrome mice","volume":"332","author":"Holm","year":"2011","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/2042-6410-1-2","article-title":"Sex-specific modification of progesterone receptor expression by 17beta-oestradiol in human cardiac tissues","volume":"1","author":"Kararigas","year":"2010","journal-title":"Biol. Sex Differ."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.jacc.2011.09.054","article-title":"Transcriptome characterization of estrogen-treated human myocardium identifies Myosin regulatory light chain interacting protein as a sex-specific element influencing contractile function","volume":"59","author":"Kararigas","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1210\/en.2013-2180","article-title":"Genetic background defines the regulation of postnatal cardiac growth by 17beta-estradiol through a beta-catenin mechanism","volume":"155","author":"Kararigas","year":"2014","journal-title":"Endocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Esslinger, U., Garnier, S., Korniat, A., Proust, C., Kararigas, G., Muller-Nurasyid, M., Empana, J.P., Morley, M.P., Perret, C., and Stark, K. (2017). Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172995"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1042\/CS20160379","article-title":"En route to precision medicine through the integration of biological sex into pharmacogenomics","volume":"131","author":"Gaignebet","year":"2017","journal-title":"Clin. Sci. (Lond.)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1111\/jcmm.14137","article-title":"An integrative systems approach identifies novel candidates in Marfan syndrome-related pathophysiology","volume":"23","author":"Bhushan","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1161\/CIRCULATIONAHA.105.601674","article-title":"Induction of macrophage chemotaxis by aortic extracts of the mgR Marfan mouse model and a GxxPG-containing fibrillin-1 fragment","volume":"114","author":"Guo","year":"2006","journal-title":"Circulation"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/jbmr.2539","article-title":"Establishing biomechanical mechanisms in mouse models: Practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones","volume":"30","author":"Jepsen","year":"2015","journal-title":"J. Bone Min. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/prca.201500031","article-title":"Effects of aging on cardiac extracellular matrix in men and women","volume":"10","author":"Dworatzek","year":"2016","journal-title":"Proteom. Clin. Appl."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3277","DOI":"10.1111\/jcmm.13231","article-title":"Folic acid reduces doxorubicin-induced cardiomyopathy by modulating endothelial nitric oxide synthase","volume":"21","author":"Octavia","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13293-019-0222-1","article-title":"Sex-specific regulation of cardiac microRNAs targeting mitochondrial proteins in pressure overload","volume":"10","author":"Queiros","year":"2019","journal-title":"Biol. Sex Differ."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1046\/j.1523-1755.1999.00770.x","article-title":"Angiotensin II type 1 receptor gene polymorphism predicts response to losartan and angiotensin II","volume":"56","author":"Miller","year":"1999","journal-title":"Kidney Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/FPC.0b013e32833a6d4a","article-title":"A single-nucleotide polymorphism of alanine to threonine at position 163 of the human angiotensin II type 1 receptor impairs Losartan affinity","volume":"20","author":"Arsenault","year":"2010","journal-title":"Pharm. Genom."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1097\/00008480-200202000-00006","article-title":"Marfan syndrome: Orthopedic and genetic review","volume":"14","author":"Giampietro","year":"2002","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1186\/s12967-018-1612-6","article-title":"Large-scale in silico identification of drugs exerting sex-specific effects in the heart","volume":"16","author":"Cui","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.jgg.2018.07.002","article-title":"The DrugPattern tool for drug set enrichment analysis and its prediction for beneficial effects of oxLDL on type 2 diabetes","volume":"45","author":"Huang","year":"2018","journal-title":"J. Genet. Genom."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/6059\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:39:06Z","timestamp":1760189946000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/6059"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,1]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["ijms20236059"],"URL":"https:\/\/doi.org\/10.3390\/ijms20236059","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,1]]}}}