{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T12:02:04Z","timestamp":1778587324189,"version":"3.51.4"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"Inactivation of the tumor suppressor p53 (encoded by the Trp53<\/jats:italic> gene) is relevant for development and growth of different cancers, including osteosarcoma, a primary bone tumor mostly affecting children and young adolescents. We have previously shown that deficiency of the ribosomal S6 kinase 2 (Rsk2) limits osteosarcoma growth in a transgenic mouse model overexpressing the proto-oncogene c-Fos<\/jats:italic>. Our initial aim for the present study was to address the question, if Rsk2 deficiency would also influence osteosarcoma growth in another mouse model. For that purpose, we took advantage of Trp53<\/jats:italic>fl\/fl<\/jats:italic><\/jats:sup> mice, which were crossed with Runx2<\/jats:italic>Cre<\/jats:italic><\/jats:sup> transgenic mice in order to inactivate p53 specifically in osteoblast lineage cells. However, since we unexpectedly identified Runx2<\/jats:italic>Cre<\/jats:italic><\/jats:sup>-mediated recombination also in the thymus, the majority of 6-month-old Trp53<\/jats:italic>fl\/fl<\/jats:italic>;Runx2-Cre<\/jats:italic><\/jats:sup> (thereafter termed Trp53<\/jats:italic>Cre<\/jats:italic><\/jats:sup>) animals displayed thymic lymphomas, similar to what has been described for Trp53<\/jats:italic>-deficient mice. Since we did not detect osteosarcoma formation at that age, we could not follow our initial aim, but we studied the skeletal phenotype of Trp53<\/jats:italic>Cre<\/jats:italic><\/jats:sup> mice, with or without additional Rsk2 deficiency. Here we unexpectedly observed that Trp53<\/jats:italic>Cre<\/jats:italic><\/jats:sup> mice display a unique accumulation of trabecular bone in the midshaft region of the femur and the humerus, consistent with its previously established role as a negative regulator of osteoblastogenesis. Since this local bone mass increase in Trp53<\/jats:italic>Cre<\/jats:italic><\/jats:sup> mice was significantly reduced by Rsk2 deficiency, we isolated bone marrow cells from the different groups of mice and analyzed their behavior ex vivo<\/jats:italic>. Here we observed a remarkable increase of colony formation, osteogenic differentiation and proliferation in Trp53<\/jats:italic>Cre<\/jats:italic><\/jats:sup> cultures, which was unaffected by Rsk2 deficiency. Our data thereby confirm a critical and tumorigenesis-independent function of p53 as a key regulator of mesenchymal cell differentiation.<\/jats:p>","DOI":"10.1371\/journal.pone.0249894","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T19:00:17Z","timestamp":1637262017000},"page":"e0249894","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Osteoblast-specific inactivation of p53 results in locally increased bone formation"],"prefix":"10.1371","volume":"16","author":[{"given":"Nannan","family":"Liao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Till","family":"Koehne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Tuckermann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioanna","family":"Triviai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Amling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Pierre","family":"David","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-0177","authenticated-orcid":true,"given":"Thorsten","family":"Schinke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Luther","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,11,18]]},"reference":[{"issue":"4","key":"pone.0249894.ref001","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nrm2147","article-title":"p53 in health and disease","volume":"8","author":"KH Vousden","year":"2007","journal-title":"Nature reviews Molecular cell biology"},{"issue":"6","key":"pone.0249894.ref002","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/humu.22559","article-title":"Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome","volume":"35","author":"J Kamihara","year":"2014","journal-title":"Human mutation"},{"issue":"1","key":"pone.0249894.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0960-9822(00)00002-6","article-title":"Tumor spectrum analysis in p53-mutant mice","volume":"4","author":"T Jacks","year":"1994","journal-title":"Current biology: CB"},{"issue":"9","key":"pone.0249894.ref004","doi-asserted-by":"crossref","first-page":"e0137745","DOI":"10.1371\/journal.pone.0137745","article-title":"The Protein Tyrosine Phosphatase Rptp\u03b6 Suppresses Osteosarcoma Development in Trp53-Heterozygous Mice","volume":"10","author":"C Baldauf","year":"2015","journal-title":"PloS one"},{"issue":"6","key":"pone.0249894.ref005","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.cmet.2010.05.005","article-title":"Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor","volume":"11","author":"A Rauch","year":"2010","journal-title":"Cell metabolism"},{"issue":"2","key":"pone.0249894.ref006","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1042\/BJ20110289","article-title":"Regulation and function of the RSK family of protein kinases","volume":"441","author":"Y Romeo","year":"2012","journal-title":"Biochem J"},{"issue":"3","key":"pone.0249894.ref007","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s12272-016-0880-z","article-title":"RSK2 and its binding partners in cell proliferation, transformation and cancer development","volume":"40","author":"YY Cho","year":"2017","journal-title":"Archives of pharmacal research"},{"issue":"6","key":"pone.0249894.ref008","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/ejhg.2009.189","article-title":"Coffin-Lowry syndrome","volume":"18","author":"PM Pereira","year":"2010","journal-title":"European journal of human genetics: EJHG"},{"key":"pone.0249894.ref009","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3389\/fnbeh.2018.00106","article-title":"Animal Models for Coffin-Lowry Syndrome: RSK2 and Nervous System Dysfunction","volume":"12","author":"M Fischer","year":"2018","journal-title":"Frontiers in behavioral neuroscience"},{"issue":"3","key":"pone.0249894.ref010","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0092-8674(04)00344-7","article-title":"ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome","volume":"117","author":"X Yang","year":"2004","journal-title":"Cell"},{"issue":"3","key":"pone.0249894.ref011","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1172\/JCI200522877","article-title":"Essential role of RSK2 in c-Fos-dependent osteosarcoma development","volume":"115","author":"JP David","year":"2005","journal-title":"The Journal of clinical investigation"},{"issue":"7","key":"pone.0249894.ref012","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1177\/0022034516634329","article-title":"Rsk2, the Kinase Mutated in Coffin-Lowry Syndrome, Controls Cementum Formation","volume":"95","author":"T Koehne","year":"2016","journal-title":"Journal of dental research"},{"issue":"3","key":"pone.0249894.ref013","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1083\/jcb.122.3.685","article-title":"Osteoblasts are target cells for transformation in c-fos transgenic mice","volume":"122","author":"AE Grigoriadis","year":"1993","journal-title":"The Journal of cell biology"},{"issue":"7","key":"pone.0249894.ref014","first-page":"1493","article-title":"Phosphorylation of c-Fos at the C-terminus enhances its transforming activity","volume":"12","author":"RH Chen","year":"1996","journal-title":"Oncogene"},{"issue":"8","key":"pone.0249894.ref015","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/ncb822","article-title":"Molecular interpretation of ERK signal duration by immediate early gene products","volume":"4","author":"LO Murphy","year":"2002","journal-title":"Nature cell biology"},{"issue":"6","key":"pone.0249894.ref016","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.ccell.2018.05.003","article-title":"Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling","volume":"33","author":"D Dhar","year":"2018","journal-title":"Cancer Cell"},{"issue":"7","key":"pone.0249894.ref017","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1002\/jbmr.2461","article-title":"The Anti-Osteoanabolic Function of Sclerostin Is Blunted in Mice Carrying a High Bone Mass Mutation of Lrp5","volume":"30","author":"TA Yorgan","year":"2015","journal-title":"Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research"},{"issue":"7","key":"pone.0249894.ref018","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/jbmr.141","article-title":"Guidelines for assessment of bone microstructure in rodents using micro-computed tomography","volume":"25","author":"ML Bouxsein","year":"2010","journal-title":"Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research"},{"issue":"1","key":"pone.0249894.ref019","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jbmr.1805","article-title":"Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee","volume":"28","author":"DW Dempster","year":"2013","journal-title":"Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research"},{"issue":"1","key":"pone.0249894.ref020","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1083\/jcb.200507106","article-title":"p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling","volume":"172","author":"X Wang","year":"2006","journal-title":"The Journal of cell biology"},{"issue":"1","key":"pone.0249894.ref021","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41418-020-0590-4","article-title":"Loss of p53 in mesenchymal stem cells promotes alteration of bone remodeling through negative regulation of osteoprotegerin","volume":"28","author":"T Velletri","year":"2021","journal-title":"Cell Death Differ"},{"issue":"3","key":"pone.0249894.ref022","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.tig.2011.12.002","article-title":"The p53 network: cellular and systemic DNA damage responses in aging and cancer","volume":"28","author":"HC Reinhardt","year":"2012","journal-title":"Trends in genetics: TIG"},{"issue":"1","key":"pone.0249894.ref023","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/sj.onc.1205020","article-title":"Caspase 9 is required for p53-dependent apoptosis and chemosensitivity in a human ovarian cancer cell line","volume":"21","author":"GS Wu","year":"2002","journal-title":"Oncogene"},{"issue":"9","key":"pone.0249894.ref024","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1158\/0008-5472.CAN-04-3935","article-title":"The p53 protein is a novel substrate of ribosomal S6 kinase 2 and a critical intermediary for ribosomal S6 kinase 2 and histone H3 interaction","volume":"65","author":"YY Cho","year":"2005","journal-title":"Cancer research"},{"issue":"8","key":"pone.0249894.ref025","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12082130","article-title":"Molecular Biology of Osteosarcoma","volume":"12","author":"AM Czarnecka","year":"2020","journal-title":"Cancers"},{"issue":"1","key":"pone.0249894.ref026","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1359\/jbmr.2002.17.1.119","article-title":"Disruption of the p53 gene results in preserved trabecular bone mass and bone formation after mechanical unloading","volume":"17","author":"A Sakai","year":"2002","journal-title":"Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research"},{"issue":"6","key":"pone.0249894.ref027","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1083\/jcb.200508130","article-title":"Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling","volume":"172","author":"CJ Lengner","year":"2006","journal-title":"The Journal of cell biology"},{"issue":"11","key":"pone.0249894.ref028","doi-asserted-by":"crossref","first-page":"e3707","DOI":"10.1371\/journal.pone.0003707","article-title":"p53 plays a role in mesenchymal differentiation programs, in a cell fate dependent manner","volume":"3","author":"A Molchadsky","year":"2008","journal-title":"PloS one"},{"issue":"20","key":"pone.0249894.ref029","doi-asserted-by":"crossref","first-page":"6107","DOI":"10.1158\/0008-5472.CAN-16-0621","article-title":"WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma","volume":"76","author":"S Del Mare","year":"2016","journal-title":"Cancer research"},{"issue":"3","key":"pone.0249894.ref030","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1002\/jcb.22749","article-title":"p53 control of bone remodeling","volume":"111","author":"H Liu","year":"2010","journal-title":"Journal of cellular biochemistry"},{"key":"pone.0249894.ref031","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.bone.2015.04.035","article-title":"Bone development","volume":"80","author":"AD Berendsen","year":"2015","journal-title":"Bone"},{"issue":"5","key":"pone.0249894.ref032","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1210\/er.2018-00050","article-title":"Regulation of Skeletal Homeostasis","volume":"39","author":"M Zaidi","year":"2018","journal-title":"Endocrine reviews"},{"key":"pone.0249894.ref033","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1146\/annurev.cellbio.042308.113308","article-title":"Genetic control of bone formation","volume":"25","author":"G Karsenty","year":"2009","journal-title":"Annual review of cell and developmental biology"},{"key":"pone.0249894.ref034","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.abb.2014.06.017","article-title":"The Great Beauty of the osteoclast","volume":"558","author":"A Cappariello","year":"2014","journal-title":"Archives of biochemistry and biophysics"},{"key":"pone.0249894.ref035","first-page":"115628","article-title":"Re-thinking the bone remodeling cycle mechanism and the origin of bone loss","volume":"2020","author":"JM Delaisse","journal-title":"Bone"},{"issue":"3","key":"pone.0249894.ref036","first-page":"347","article-title":"Biological basis of bone strength: anatomy, physiology and measurement","volume":"20","author":"NH Hart","year":"2020","journal-title":"Journal of musculoskeletal & neuronal interactions"},{"key":"pone.0249894.ref037","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fendo.2016.00127","article-title":"The Bone Marrow-Derived Stromal Cells: Commitment and Regulation of Adipogenesis","volume":"7","author":"M Tencerova","year":"2016","journal-title":"Frontiers in endocrinology"},{"issue":"10","key":"pone.0249894.ref038","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/s41577-019-0178-8","article-title":"Osteoimmunology: evolving concepts in bone-immune interactions in health and disease","volume":"19","author":"M Tsukasaki","year":"2019","journal-title":"Nat Rev Immunol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249894","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T19:00:59Z","timestamp":1637262059000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0249894"}},"subtitle":[],"editor":[{"given":"Andre","family":"van Wijnen","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0249894","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]}}}