{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:49:03Z","timestamp":1792784943833,"version":"4.5.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T00:00:00Z","timestamp":1765584000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":45,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2019-01852"],"award-info":[{"award-number":["2019-01852"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006285","name":"Magnus Bergvalls Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006285","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008444","name":"O. E. och Edla Johanssons Vetenskapliga Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008444","id-type":"DOI","asserted-by":"publisher"}]},{"name":"This study was supported by the Swedish state under the agreement between the Swedish government and the country councils, the ALF agreement"},{"name":"This study was supported by the Swedish state under the agreement between the Swedish government and the country councils, the ALF agreement"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Irradiation is an effective therapy for eliminating cancer cells and serves as a critical preparative regimen for hematopoietic stem cell transplantation (HSCT). However, irradiation affects healthy tissue, disrupting bone tissue and bone marrow homeostasis, which leads to skeletal and immune dysfunction. To investigate these effects, we used a female murine model to explore the mechanisms underlying the skeletal damage caused by total body irradiation. Experiments were carried out over a 12-week period of total body irradiation and HSCT, supplemented by an acute study involving only total body irradiation and osteoclastogenesis. Irradiation resulted in a depletion of bone marrow immune cells, followed by an increase in bone marrow cellularity 12 weeks after irradiation and HSCT compared to naive controls, indicating late-stage local immune induction. Cortical and trabecular bone loss appeared 2 weeks post-irradiation and HSCT and persisted throughout the study. This bone damage was accompanied by a sustained increase in apoptotic cells in the bone marrow within 6\u2009h post-irradiation and persisted for up to 12 weeks after irradiation and HSCT. This was coupled with elevated local expression of the pro-apoptotic\n                    <jats:italic>Bax<\/jats:italic>\n                    gene and an increase in\n                    <jats:italic>TGF-\u03b21<\/jats:italic>\n                    , a gene associated with the clearance of apoptotic cells. In vitro studies demonstrated that macrophages and pre-osteoclasts, but not fully differentiated osteoclasts, efficiently cleared apoptotic cells, resulting in increased levels of TGF-\u03b21 in the culture supernatant. While the clearance of apoptotic cells and associated TGF-\u03b21 signaling were evident, their direct role in skeletal outcomes remains unclear. These findings suggest that persistent apoptotic cells contribute to impaired bone remodeling, potentially affecting osteoclast function and the bone microenvironment. Additional research is needed to investigate whether targeting apoptotic cell clearance can mitigate bone damage and promote skeletal recovery following irradiation.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08303-7","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T13:37:09Z","timestamp":1765633029000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Disrupted bone microenvironment and immune recovery following total body irradiation in a murine model"],"prefix":"10.1038","volume":"17","author":[{"given":"Tibor","family":"S\u00e1ghy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priti","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Horkeby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Henning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claes","family":"Ohlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1865-3494","authenticated-orcid":false,"given":"Carmen","family":"Corciulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie K.","family":"Lagerquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2696-5850","authenticated-orcid":false,"given":"Andrei S.","family":"Chagin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8914-0178","authenticated-orcid":false,"given":"Cecilia","family":"Engdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,13]]},"reference":[{"key":"8303_CR1","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1002\/cncr.21324","volume":"104","author":"G Delaney","year":"2005","unstructured":"Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104:1129\u201337.","journal-title":"Cancer"},{"key":"8303_CR2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13018-015-0339-9","volume":"11","author":"Q Zou","year":"2016","unstructured":"Zou Q, Hong W, Zhou Y, Ding Q, Wang J, Jin W, et al. Bone marrow stem cell dysfunction in radiation-induced abscopal bone loss. J Orthop Surg Res. 2016;11:3.","journal-title":"J Orthop Surg Res"},{"key":"8303_CR3","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.joms.2015.07.009","volume":"74","author":"MM Curi","year":"2016","unstructured":"Curi MM, Cardoso CL, de Lima HG, Kowalski LP, Martins MD. Histopathologic and histomorphometric analysis of irradiation injury in bone and the surrounding soft tissues of the jaws. J Oral Maxillofac Surg. 2016;74:190\u20139.","journal-title":"J Oral Maxillofac Surg"},{"key":"8303_CR4","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/s41413-023-00273-w","volume":"11","author":"F Wei","year":"2023","unstructured":"Wei F, Tuong ZK, Omer M, Ngo C, Asiatico J, Kinzel M, et al. A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss. Bone Res. 2023;11:34.","journal-title":"Bone Res"},{"key":"8303_CR5","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1634\/theoncologist.11-10-1121","volume":"11","author":"TA Guise","year":"2006","unstructured":"Guise TA. Bone loss and fracture risk associated with cancer therapy. Oncologist. 2006;11:1121\u201331.","journal-title":"Oncologist"},{"key":"8303_CR6","doi-asserted-by":"publisher","first-page":"3635","DOI":"10.1182\/blood-2003-09-3081","volume":"103","author":"CM Schulte","year":"2004","unstructured":"Schulte CM, Beelen DW. Bone loss following hematopoietic stem cell transplantation: a long-term follow-up. Blood. 2004;103:3635\u201343.","journal-title":"Blood"},{"key":"8303_CR7","doi-asserted-by":"publisher","first-page":"95","DOI":"10.3857\/roj.2023.00969","volume":"42","author":"L Berk","year":"2024","unstructured":"Berk L. The effects of high-dose radiation therapy on bone: a scoping review. Radiat Oncol J. 2024;42:95\u2013103.","journal-title":"Radiat Oncol J"},{"key":"8303_CR8","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1007\/s00198-024-07171-9","volume":"35","author":"P Johansson","year":"2024","unstructured":"Johansson P, Kristjansdottir HL, Johansson H, Mellstrom D, Lewerin C. Increased risk of hip and major osteoporotic fractures in 8463 patients who have undergone stem cell transplantation, a Swedish population-based study. Osteoporos Int. 2024;35:1831\u20138.","journal-title":"Osteoporos Int"},{"key":"8303_CR9","doi-asserted-by":"crossref","unstructured":"McNally M, Corrigan R, Sliepen J, Dudareva M, Rentenaar R, Frank IJ, et al. What factors affect outcome in the treatment of fracture-related infection? Antibiotics. 2022;11:946.","DOI":"10.3390\/antibiotics11070946"},{"key":"8303_CR10","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1201500","volume":"13","author":"H Paganetti","year":"2023","unstructured":"Paganetti H. A review on lymphocyte radiosensitivity and its impact on radiotherapy. Front Oncol. 2023;13:1201500.","journal-title":"Front Oncol"},{"key":"8303_CR11","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1111\/imcb.12206","volume":"97","author":"SM Gheibi Hayat","year":"2019","unstructured":"Gheibi Hayat SM, Bianconi V, Pirro M, Sahebkar A. Efferocytosis: molecular mechanisms and pathophysiological perspectives. Immunol Cell Biol. 2019;97:124\u201333.","journal-title":"Immunol Cell Biol"},{"key":"8303_CR12","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.4049\/jimmunol.1601520","volume":"198","author":"MR Elliott","year":"2017","unstructured":"Elliott MR, Koster KM, Murphy PS. Efferocytosis signaling in the regulation of macrophage inflammatory responses. J Immunol. 2017;198:1387\u201394.","journal-title":"J Immunol"},{"key":"8303_CR13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1415573","volume":"15","author":"Y Ma","year":"2024","unstructured":"Ma Y, Jiang T, Zhu X, Xu Y, Wan K, Zhang T, et al. Efferocytosis in dendritic cells: an overlooked immunoregulatory process. Front Immunol. 2024;15:1415573.","journal-title":"Front Immunol"},{"key":"8303_CR14","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1423-0127-19-28","volume":"19","author":"J Zupan","year":"2012","unstructured":"Zupan J, Komadina R, Marc J. The relationship between osteoclastogenic and anti-osteoclastogenic pro-inflammatory cytokines differs in human osteoporotic and osteoarthritic bone tissues. J Biomed Sci. 2012;19:28.","journal-title":"J Biomed Sci"},{"key":"8303_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-81058-1","volume":"11","author":"D Heylmann","year":"2021","unstructured":"Heylmann D, Ponath V, Kindler T, Kaina B. Comparison of DNA repair and radiosensitivity of different blood cell populations. Sci Rep. 2021;11:2478.","journal-title":"Sci Rep"},{"key":"8303_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05931-9","volume":"14","author":"ER Quarato","year":"2023","unstructured":"Quarato ER, Salama NA, Li AJ, Smith CO, Zhang J, Kawano Y, et al. Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling. Cell Death Dis. 2023;14:428.","journal-title":"Cell Death Dis"},{"key":"8303_CR17","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1182\/blood-2009-11-255026","volume":"116","author":"H Li","year":"2010","unstructured":"Li H, Hong S, Qian J, Zheng Y, Yang J, Yi Q. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood. 2010;116:210\u20137.","journal-title":"Blood"},{"key":"8303_CR18","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.3389\/fimmu.2019.01408","volume":"10","author":"MB Madel","year":"2019","unstructured":"Madel MB, Ib\u00e1\u00f1ez L, Wakkach A, de Vries TJ, Teti A, Apparailly F, et al. Immune function and diversity of osteoclasts in normal and pathological conditions. Front Immunol. 2019;10:1408.","journal-title":"Front Immunol"},{"key":"8303_CR19","doi-asserted-by":"publisher","first-page":"612","DOI":"10.3109\/08916934.2012.719950","volume":"45","author":"U Harre","year":"2012","unstructured":"Harre U, Keppeler H, Ipseiz N, Derer A, Poller K, Aigner M, et al. Moonlighting osteoclasts as undertakers of apoptotic cells. Autoimmunity. 2012;45:612\u20139.","journal-title":"Autoimmunity"},{"key":"8303_CR20","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/s41413-024-00341-9","volume":"12","author":"L Batoon","year":"2024","unstructured":"Batoon L, Koh AJ, Millard SM, Grewal J, Choo FM, Kannan R, et al. Induction of osteoblast apoptosis stimulates macrophage efferocytosis and paradoxical bone formation. Bone Res. 2024;12:43.","journal-title":"Bone Res"},{"key":"8303_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03059-8","volume":"11","author":"JY Ru","year":"2020","unstructured":"Ru JY, Wang YF. Osteocyte apoptosis: the roles and key molecular mechanisms in resorption-related bone diseases. Cell Death Dis. 2020;11:846.","journal-title":"Cell Death Dis"},{"key":"8303_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05594-6","volume":"14","author":"L Batoon","year":"2023","unstructured":"Batoon L, Koh AJ, Kannan R, McCauley LK, Roca H. Caspase-9 driven murine model of selective cell apoptosis and efferocytosis. Cell Death Dis. 2023;14:58.","journal-title":"Cell Death Dis"},{"key":"8303_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06211-2","volume":"14","author":"S Liu","year":"2023","unstructured":"Liu S, Wang W, Hu S, Jia B, Tuo B, Sun H, et al. Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity. Cell Death Dis. 2023;14:679.","journal-title":"Cell Death Dis"},{"key":"8303_CR24","doi-asserted-by":"publisher","first-page":"5169.","DOI":"10.3390\/ijms21145169","volume":"21","author":"H Kitaura","year":"2020","unstructured":"Kitaura H, Marahleh A, Ohori F, Noguchi T, Shen WR, Qi J, et al. Osteocyte-related cytokines regulate osteoclast formation and bone resorption. Int J Mol Sci. 2020;21:5169.","journal-title":"Int J Mol Sci"},{"key":"8303_CR25","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1158\/0008-5472.CAN-14-3511","volume":"75","author":"C Vanpouille-Box","year":"2015","unstructured":"Vanpouille-Box C, Diamond JM, Pilones KA, Zavadil J, Babb JS, Formenti SC, et al. TGFbeta Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity. Cancer Res. 2015;75:2232\u201342.","journal-title":"Cancer Res"},{"key":"8303_CR26","doi-asserted-by":"crossref","unstructured":"Jann J, Gascon S, Roux S, Faucheux N. Influence of the TGF-beta Superfamily on Osteoclasts\/Osteoblasts Balance in Physiological and Pathological Bone Conditions. Int J Mol Sci. 2020;21.","DOI":"10.3390\/ijms21207597"},{"key":"8303_CR27","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1038\/nature01658","volume":"423","author":"WJ Boyle","year":"2003","unstructured":"Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:337\u201342.","journal-title":"Nature"},{"key":"8303_CR28","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1007\/978-1-4939-2966-5_18","volume":"1344","author":"JL Crane","year":"2016","unstructured":"Crane JL, Xian L, Cao X. Role of TGF-beta signaling in coupling bone remodeling. Methods Mol Biol. 2016;1344:287\u2013300.","journal-title":"Methods Mol Biol"},{"key":"8303_CR29","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.bone.2018.12.006","volume":"120","author":"A Chandra","year":"2019","unstructured":"Chandra A, Park SS, Pignolo RJ. Potential role of senescence in radiation-induced damage of the aged skeleton. Bone. 2019;120:423\u201331.","journal-title":"Bone"},{"key":"8303_CR30","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/jbmr.2996","volume":"32","author":"A Chandra","year":"2017","unstructured":"Chandra A, Lin T, Young T, Tong W, Ma X, Tseng WJ, et al. Suppression of sclerostin alleviates radiation-induced bone loss by protecting bone-forming cells and their progenitors through distinct mechanisms. J Bone Min Res. 2017;32:360\u201372.","journal-title":"J Bone Min Res"},{"key":"8303_CR31","doi-asserted-by":"publisher","first-page":"E589","DOI":"10.1152\/ajpendo.00255.2014","volume":"307","author":"P Henning","year":"2014","unstructured":"Henning P, Ohlsson C, Engdahl C, Farman H, Windahl SH, Carlsten H, et al. The effect of estrogen on bone requires ERalpha in nonhematopoietic cells but is enhanced by ERalpha in hematopoietic cells. Am J Physiol Endocrinol Metab. 2014;307:E589\u201395.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"8303_CR32","doi-asserted-by":"publisher","first-page":"e1413","DOI":"10.1210\/clinem\/dgab867","volume":"107","author":"C Ohlsson","year":"2022","unstructured":"Ohlsson C, Langenski\u00f6ld M, Smidfelt K, Poutanen M, Ryberg H, Norl\u00e9n AK, et al. Low progesterone and low estradiol levels associate with abdominal aortic aneurysms in men. J Clin Endocrinol Metab. 2022;107:e1413\u201325.","journal-title":"J Clin Endocrinol Metab"},{"key":"8303_CR33","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1002\/2211-5463.12584","volume":"9","author":"Z Budai","year":"2019","unstructured":"Budai Z, Ujlaky-Nagy L, Kis GN, Antal M, Banko C, Bacso Z, et al. Macrophages engulf apoptotic and primary necrotic thymocytes through similar phosphatidylserine-dependent mechanisms. FEBS Open Bio. 2019;9:446\u201356.","journal-title":"FEBS Open Bio"},{"key":"8303_CR34","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1002\/jbmr.3978","volume":"35","author":"A Chandra","year":"2020","unstructured":"Chandra A, Lagnado AB, Farr JN, Monroe DG, Park S, Hachfeld C, et al. Targeted reduction of senescent cell burden alleviates focal radiotherapy-related bone loss. J Bone Min Res. 2020;35:1119\u201331.","journal-title":"J Bone Min Res"},{"key":"8303_CR35","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo5217","volume":"15","author":"W Guo","year":"2023","unstructured":"Guo W, Hoque J, Garcia Garcia CJ, Spiller KV, Leinroth AP, Puviindran V, et al. Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2\u03b1 in skeletal progenitor cells. Sci Transl Med. 2023;15:eabo5217.","journal-title":"Sci Transl Med"},{"key":"8303_CR36","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1053\/bbmt.2001.v7.pm11400947","volume":"7","author":"JM Stern","year":"2001","unstructured":"Stern JM, Sullivan KM, Ott SM, Seidel K, Fink JC, Longton G, et al. Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study. Biol Blood Marrow Transplant. 2001;7:257\u201364.","journal-title":"Biol Blood Marrow Transplant"},{"key":"8303_CR37","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/16852","volume":"397","author":"YY Kong","year":"1999","unstructured":"Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397:315\u201323.","journal-title":"Nature"},{"key":"8303_CR38","doi-asserted-by":"publisher","first-page":"3839","DOI":"10.1182\/blood-2006-07-037994","volume":"109","author":"Y Li","year":"2007","unstructured":"Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian WP, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109:3839\u201348.","journal-title":"Blood"},{"key":"8303_CR39","doi-asserted-by":"publisher","first-page":"e163704.","DOI":"10.1172\/jci.insight.163704","volume":"8","author":"MJ Griffiths","year":"2023","unstructured":"Griffiths MJ, Marshall SA, Cousins FL, Alesi LR, Higgins J, Giridharan S, et al. Radiotherapy exposure directly damages the uterus and causes pregnancy loss. JCI Insight. 2023;8:e163704.","journal-title":"JCI Insight"},{"key":"8303_CR40","first-page":"247","volume":"578","author":"CJ Lee","year":"2005","unstructured":"Lee CJ, Yoon YD. Gamma-radiation-induced follicular degeneration in the prepubertal mouse ovary. Mutat Res. 2005;578:247\u201355.","journal-title":"Mutat Res"},{"key":"8303_CR41","doi-asserted-by":"publisher","first-page":"2631","DOI":"10.1182\/blood-2004-06-2480","volume":"105","author":"RS Taichman","year":"2005","unstructured":"Taichman RS. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood. 2005;105:2631\u20139.","journal-title":"Blood"},{"key":"8303_CR42","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1093\/jrr\/rrx026","volume":"58","author":"J Zhang","year":"2017","unstructured":"Zhang J, Wang Z, Wu A, Nie J, Pei H, Hu W, et al. Differences in responses to X-ray exposure between osteoclast and osteoblast cells. J Radiat Res. 2017;58:791\u2013802.","journal-title":"J Radiat Res"},{"key":"8303_CR43","doi-asserted-by":"publisher","first-page":"6377.","DOI":"10.3390\/ijms21176377","volume":"21","author":"AJ Donaubauer","year":"2020","unstructured":"Donaubauer AJ, Deloch L, Becker I, Fietkau R, Frey B, Gaipl US. The influence of radiation on bone and bone cells-differential effects on osteoclasts and osteoblasts. Int J Mol Sci. 2020;21:6377.","journal-title":"Int J Mol Sci"},{"key":"8303_CR44","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/6529","volume":"5","author":"EM Horwitz","year":"1999","unstructured":"Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 1999;5:309\u201313.","journal-title":"Nat Med"},{"key":"8303_CR45","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1111\/j.1365-2796.2012.02564.x","volume":"272","author":"M Kawai","year":"2012","unstructured":"Kawai M, de Paula FJ, Rosen CJ. New insights into osteoporosis: the bone-fat connection. J Intern Med. 2012;272:317\u201329.","journal-title":"J Intern Med"},{"key":"8303_CR46","doi-asserted-by":"publisher","first-page":"279","DOI":"10.4067\/S0716-97602012000300009","volume":"45","author":"AM Pino","year":"2012","unstructured":"Pino AM, Rosen CJ, Rodriguez JP. In osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis. Biol Res. 2012;45:279\u201387.","journal-title":"Biol Res"},{"key":"8303_CR47","doi-asserted-by":"publisher","first-page":"3212","DOI":"10.1089\/ten.tea.2013.0663","volume":"20","author":"S Herberg","year":"2014","unstructured":"Herberg S, Kondrikova G, Hussein KA, Periyasamy-Thandavan S, Johnson MH, Elsalanty ME, et al. Total body irradiation is permissive for mesenchymal stem cell-mediated new bone formation following local transplantation. Tissue Eng Part A. 2014;20:3212\u201327.","journal-title":"Tissue Eng Part A"},{"key":"8303_CR48","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1055\/s-2001-15109","volume":"109","author":"S Hering","year":"2001","unstructured":"Hering S, Isken E, Knabbe C, Janott J, Jost C, Pommer A, et al. TGFbeta1 and TGFbeta2 mRNA and protein expression in human bone samples. Exp Clin Endocrinol Diabetes. 2001;109:217\u201326.","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"8303_CR49","doi-asserted-by":"publisher","first-page":"757","DOI":"10.1038\/nm.1979","volume":"15","author":"Y Tang","year":"2009","unstructured":"Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, et al. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med. 2009;15:757\u201365.","journal-title":"Nat Med"},{"key":"8303_CR50","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104745","volume":"155","author":"B Farhood","year":"2020","unstructured":"Farhood B, Khodamoradi E, Hoseini-Ghahfarokhi M, Motevaseli E, Mirtavoos-Mahyari H, Eleojo Musa A, et al. TGF-beta in radiotherapy: mechanisms of tumor resistance and normal tissues injury. Pharmacol Res. 2020;155:104745.","journal-title":"Pharmacol Res"},{"key":"8303_CR51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2021.155709","volume":"148","author":"J Wang","year":"2021","unstructured":"Wang J, Xu Z, Wang Z, Du G, Lun L. TGF-beta signaling in cancer radiotherapy. Cytokine. 2021;148:155709.","journal-title":"Cytokine"},{"key":"8303_CR52","doi-asserted-by":"publisher","first-page":"e72772","DOI":"10.1371\/journal.pone.0072772","volume":"8","author":"W Xiong","year":"2013","unstructured":"Xiong W, Frasch SC, Thomas SM, Bratton DL, Henson PM. Induction of TGF-\u03b21 synthesis by macrophages in response to apoptotic cells requires activation of the scavenger receptor CD36. PLoS ONE. 2013;8:e72772.","journal-title":"PLoS ONE"},{"key":"8303_CR53","doi-asserted-by":"publisher","first-page":"2045.","DOI":"10.3390\/ijms17122045","volume":"17","author":"T Komori","year":"2016","unstructured":"Komori T. Cell death in chondrocytes, osteoblasts, and osteocytes. Int J Mol Sci. 2016;17:2045.","journal-title":"Int J Mol Sci"},{"key":"8303_CR54","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1172\/JCI0211638","volume":"109","author":"ML Huynh","year":"2002","unstructured":"Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J Clin Invest. 2002;109:41\u201350.","journal-title":"J Clin Invest"},{"key":"8303_CR55","doi-asserted-by":"publisher","first-page":"e72772","DOI":"10.1371\/journal.pone.0072772","volume":"8","author":"W Xiong","year":"2013","unstructured":"Xiong W, Frasch SC, Thomas SM, Bratton DL, Henson PM. Induction of TGF-beta1 synthesis by macrophages in response to apoptotic cells requires activation of the scavenger receptor CD36. PLoS ONE. 2013;8:e72772.","journal-title":"PLoS ONE"},{"key":"8303_CR56","doi-asserted-by":"publisher","first-page":"5036","DOI":"10.4049\/jimmunol.180.7.5036","volume":"180","author":"N Nacu","year":"2008","unstructured":"Nacu N, Luzina IG, Highsmith K, Lockatell V, Pochetuhen K, Cooper ZA, et al. Macrophages produce TGF-beta-induced (beta-ig-h3) following ingestion of apoptotic cells and regulate MMP14 levels and collagen turnover in fibroblasts. J Immunol. 2008;180:5036\u201344.","journal-title":"J Immunol"},{"key":"8303_CR57","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.bbrc.2007.11.120","volume":"366","author":"SW Fox","year":"2008","unstructured":"Fox SW, Evans KE, Lovibond AC. Transforming growth factor-beta enables NFATc1 expression during osteoclastogenesis. Biochem Biophys Res Commun. 2008;366:123\u20138.","journal-title":"Biochem Biophys Res Commun"},{"key":"8303_CR58","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1242\/jcs.113.13.2445","volume":"113","author":"K Fuller","year":"2000","unstructured":"Fuller K, Lean JM, Bayley KE, Wani MR, Chambers TJ. A role for TGFbeta(1) in osteoclast differentiation and survival. J Cell Sci. 2000;113:2445\u201353.","journal-title":"J Cell Sci"},{"key":"8303_CR59","doi-asserted-by":"crossref","unstructured":"Xu L, Wang Y, Wang J, Zhai J, Ren L, Zhu G. Radiation-induced osteocyte senescence alters bone marrow mesenchymal stem cell differentiation potential via paracrine signaling. Int J Mol Sci. 2021;22.","DOI":"10.3390\/ijms22179323"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08303-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08303-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08303-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T18:02:50Z","timestamp":1769536970000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08303-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,13]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8303"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08303-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.03.17.643638","asserted-by":"object"}]},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,13]]},"assertion":[{"value":"31 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 October 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 December 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Ethical approval was obtained from the Gothenburg Regional Animal Ethics Committee in Sweden (case number 1\u20132017). All sample handling and procedures were carried out and reported in accordance with relevant guidelines and regulations approved by the University of Gothenburg and Swedish law.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"122"}}