{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:19:47Z","timestamp":1785406787075,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82474196"],"award-info":[{"award-number":["82474196"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82474196"],"award-info":[{"award-number":["82474196"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Radiation-induced bone injury (RIBI) is a delayed complication of radiotherapy that causes progressive bone loss and impairs skeletal integrity. In this study, we investigated whether phenylethanoid glycosides (PGs) from Cistanche tubulosa (Schenk) Wight could improve RIBI and explored the underlying mechanism. Using a mouse model of delayed radiation-induced bone injury, we found that PGs improved body weight recovery, grip strength, and oxidative stress status after irradiation. Through micro-computed tomography and histological staining to evaluate bone microstructure, it was found that PGs could reduce osteoclast activity after radiation and restore trabecular microstructure, thereby alleviating bone loss caused by radiation. Single-cell RNA sequencing of femoral bone marrow revealed that radiation disrupted the cellular composition of the bone marrow microenvironment and impaired osteogenic programs in bone marrow mesenchymal stem cells. PGs partially restored osteogenic differentiation-related signatures and suppressed adipogenic bias. In osteoblasts, we identified Gremlin-1 (Grem1), a negative regulator of BMP signaling, as a key radiation-responsive gene that was markedly upregulated after irradiation and downregulated by PGs. Western blotting in femoral tissue and MC3T3-E1 cells confirmed that PGs suppressed radiation-induced Grem1 expression. In vitro, PGs promoted alkaline phosphatase activity and mineralization in irradiated osteoblasts. These findings suggest that PGs mitigate RIBI by attenuating oxidative stress, improving bone remodeling, restoring the bone marrow microenvironment, and relieving Grem1-mediated inhibition of osteogenesis. Grem1 may represent a potential therapeutic target for radiation-associated skeletal injury.<\/jats:p>","DOI":"10.3390\/ijms27094109","type":"journal-article","created":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T07:57:29Z","timestamp":1777967849000},"page":"4109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenylethanoid Glycosides from Cistanche tubulosa (Schenk) Wight Improve Radiation-Induced Bone Injury and Reduce Grem1 Expression in Osteoblasts"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9016-2272","authenticated-orcid":false,"given":"Xiaoqiang","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3166-3694","authenticated-orcid":false,"given":"Xianxie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Ru","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenrun","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Du","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ao","family":"Kong","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Chen","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengchun","family":"Ma","sequence":"additional","affiliation":[{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuguang","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"ref_1","first-page":"vdaa057","article-title":"Radiation-induced brain injury: Current concepts and therapeutic strategies targeting neuroinflammation","volume":"2","author":"Turnquist","year":"2020","journal-title":"Neurooncol. Adv."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"rbaf118","DOI":"10.1093\/rb\/rbaf118","article-title":"Magnesium ion hydrogel enhances resistance to radiation-induced bone injury by modulating the bone immune microenvironment and promoting microvascularization","volume":"12","author":"Wang","year":"2025","journal-title":"Regen. Biomater."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5660927","DOI":"10.1155\/2021\/5660927","article-title":"Treatment of Radiation Bone Injury with Transplanted hUCB-MSCs via Wnt\/beta-Catenin","volume":"2021","author":"Zhang","year":"2021","journal-title":"Stem Cells Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1002\/jbmr.3564","article-title":"The Spectrum of Fundamental Basic Science Discoveries Contributing to Organismal Aging","volume":"33","author":"Farr","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/j.identj.2025.03.006","article-title":"Establishment of an Osteoradionecrosis Model and its Mechanism Via Single Ionizing Radiation Exposure","volume":"75","author":"Wang","year":"2025","journal-title":"Int. Dent. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"159681","DOI":"10.1016\/j.bbalip.2025.159681","article-title":"Echinacoside suppresses macrophage lipid accumulation and attenuates atherosclerosis via the MDM2\/PPARgamma\/ABCA1 signaling axis","volume":"1870","author":"Zhou","year":"2025","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1007\/s11064-019-02782-9","article-title":"Echinacoside Alleviates Hypoxic-Ischemic Brain Injury in Neonatal Rat by Enhancing Antioxidant Capacity and Inhibiting Apoptosis","volume":"44","author":"Wei","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"176715","DOI":"10.1016\/j.ejphar.2024.176715","article-title":"Acteoside delays the fibrosis process of diabetic nephropathy by anti-oxidation and regulating the autophagy-lysosome pathway","volume":"978","author":"Zhou","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3761","DOI":"10.1111\/jcmm.13285","article-title":"Echinacoside\u2019s nigrostriatal dopaminergic protection against 6-OHDA-Induced endoplasmic reticulum stress through reducing the accumulation of Seipin","volume":"21","author":"Zhang","year":"2017","journal-title":"J. Cell Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"113899","DOI":"10.1016\/j.jep.2021.113899","article-title":"Total glycosides and polysaccharides of Cistanche deserticola prevent osteoporosis by activating Wnt\/beta-catenin signaling pathway in SAMP6 mice","volume":"271","author":"Wang","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41392-025-02136-8","article-title":"Single-cell transcriptomics reveals novel chondrocyte and osteoblast subtypes and their role in knee osteoarthritis pathogenesis","volume":"10","author":"Liu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"eadl2238","DOI":"10.1126\/sciadv.adl2238","article-title":"Identification of the metaphyseal skeletal stem cell building trabecular bone","volume":"10","author":"Yang","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ru, Y., Zhang, X., Shen, B., Yang, C., Yu, H., Liu, Z., Wu, X., Li, F., Cui, J., and Lai, C. (2023). Delayed Reaction of Radiation on the Central Nervous System and Bone System in C57BL\/6J Mice. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010337"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jura-Poltorak, A., Szeremeta, A., Olczyk, K., Zon-Giebel, A., and Komosinska-Vassev, K. (2021). Bone Metabolism and RANKL\/OPG Ratio in Rheumatoid Arthritis Women Treated with TNF-alpha Inhibitors. J. Clin. Med., 10.","DOI":"10.3390\/jcm10132905"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6183","DOI":"10.2147\/DDDT.S505055","article-title":"Mechanistic Insights into Shenzhuo Formula for Diabetic Retinopathy: Integrating UPLC-Q-TOF-MS\/MS, Network Pharmacology, Single-Cell RNA Sequencing Data, and Experimental Validation","volume":"19","author":"Zang","year":"2025","journal-title":"Drug Des. Devel Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/s41556-018-0121-4","article-title":"Single-cell characterization of haematopoietic progenitors and their trajectories in homeostasis and perturbed haematopoiesis","volume":"20","author":"Giladi","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e54695","DOI":"10.7554\/eLife.54695","article-title":"Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment","volume":"9","author":"Zhong","year":"2020","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.1016\/j.cell.2015.11.013","article-title":"Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors","volume":"163","author":"Paul","year":"2015","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"He, Y., Qi, W., Xie, X., and Jiang, H. (2024). Identification and validation of a novel predictive signature based on hepatocyte-specific genes in hepatocellular carcinoma by integrated analysis of single-cell and bulk RNA sequencing. BMC Med. Genom., 17.","DOI":"10.1186\/s12920-024-01871-1"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.stem.2020.11.004","article-title":"Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis","volume":"28","author":"Leimkuhler","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107158","DOI":"10.1016\/j.jbc.2024.107158","article-title":"Refining the identity of mesenchymal cell types associated with murine periosteal and endosteal bone","volume":"300","author":"Nookaew","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/j.cell.2019.04.040","article-title":"A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia","volume":"177","author":"Baryawno","year":"2019","journal-title":"Cell"},{"key":"ref_23","first-page":"2557","article-title":"Delivery of dexamethasone from bioactive nanofiber matrices stimulates odontogenesis of human dental pulp cells through integrin\/BMP\/mTOR signaling pathways","volume":"11","author":"Lim","year":"2016","journal-title":"Int. J. Nanomed."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, Y., Yu, Y., Zhang, M., Yu, W., and Kang, L. (2024). Mechanisms of endocrine resistance in hormone receptor-positive breast cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1448687"},{"key":"ref_25","first-page":"540","article-title":"Enhanced sequential osteosarcoma therapy using a 3D-Printed bioceramic scaffold combined with 2D nanosheets via NIR-II photothermal-chemodynamic synergy","volume":"50","author":"Jian","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1021\/acsami.7b13750","article-title":"Multifunctional Copper-Containing Carboxymethyl Chitosan\/Alginate Scaffolds for Eradicating Clinical Bacterial Infection and Promoting Bone Formation","volume":"10","author":"Lu","year":"2018","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Arrieta, O., Lozano-Ruiz, F., Guijosa, A., Soberanis-Pina, P., Blake-Cerda, M., Gomez-Garcia, A.P., Maldonado-Magos, F., Conde-Flores, E., Cardona, A.F., and Perez Alvarez, S.I. (2025). Case report: Chest radiotherapy-induced vertebral fractures in lung cancer patients: A case series and literature review. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1438120"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/jbmr.2996","article-title":"Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms","volume":"32","author":"Chandra","year":"2017","journal-title":"J. Bone Miner. Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wang, Y., Ren, L., Xu, L., Wang, J., Zhai, J., and Zhu, G. (2023). Radiation Induces Bone Microenvironment Disruption by Activating the STING-TBK1 Pathway. Medicina, 59.","DOI":"10.3390\/medicina59071316"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s12929-015-0201-8","article-title":"Reactive oxygen species contribute to dysfunction of bone marrow hematopoietic stem cells in aged C57BL\/6 J mice","volume":"22","author":"Porto","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41413-024-00381-1","article-title":"Bifidobacterium animalis subsp. lactis A6 ameliorates bone and muscle loss via modulating gut microbiota composition and enhancing butyrate production","volume":"13","author":"Chen","year":"2025","journal-title":"Bone Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1002\/sctm.20-0294","article-title":"Advances in preclinical hematopoietic stem cell models and possible implications for improving therapeutic transplantation","volume":"10","author":"Fraint","year":"2021","journal-title":"Stem Cells Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1186\/s13014-023-02380-8","article-title":"A prospective single-arm study on the relationship between dose-volume parameters of pelvic functional bone marrow and acute hematological toxicities during intensity-modulated radiotherapy with or without concurrent chemotherapy for uterine cervical\/endometrial cancer","volume":"18","author":"Chen","year":"2023","journal-title":"Radiat. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"115820","DOI":"10.1016\/j.intimp.2025.115820","article-title":"Catalpol attenuates postmenopausal osteoporosis by activating SIRT1-mediated P53 deacetylation and inhibiting CASPASE-3-driven osteoblast apoptosis","volume":"168","author":"Bian","year":"2026","journal-title":"Int. Immunopharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1017\/S0007114525103875","article-title":"The research progress and potential applications of n-3 fatty acids in orthopaedics: A narrative review","volume":"134","author":"Mao","year":"2025","journal-title":"Br. J. Nutr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.gendis.2014.07.005","article-title":"Bone Morphogenetic Protein (BMP) signaling in development and human diseases","volume":"1","author":"Wang","year":"2014","journal-title":"Genes. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1196\/annals.1346.006","article-title":"BMP signaling and skeletogenesis","volume":"1068","author":"Li","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1210\/en.2004-0766","article-title":"Skeletal overexpression of gremlin impairs bone formation and causes osteopenia","volume":"146","author":"Gazzerro","year":"2005","journal-title":"Endocrinology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/s12276-022-00753-9","article-title":"Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-beta-mediated Smad2\/3 phosphorylation","volume":"54","author":"Chen","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1136\/annrheumdis-2020-218350","article-title":"Identification of the skeletal progenitor cells forming osteophytes in osteoarthritis","volume":"79","author":"Roelofs","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/s41467-019-09491-5","article-title":"Excessive mechanical loading promotes osteoarthritis through the gremlin-1\u2013NF-\u03baB pathway","volume":"10","author":"Chang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1101\/gad.300053.117","article-title":"The SIAH E3 ubiquitin ligases promote Wnt\/beta-catenin signaling through mediating Wnt-induced Axin degradation","volume":"31","author":"Ji","year":"2017","journal-title":"Genes. Dev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/4109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T04:37:41Z","timestamp":1778560661000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/9\/4109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,4]]},"references-count":42,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27094109"],"URL":"https:\/\/doi.org\/10.3390\/ijms27094109","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,4]]}}}