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However, the precise mechanisms that drive its development remain largely unknown, and no effective medical countermeasure exists. Deciphering the molecular mechanism and mode of action as well as discerning molecular biomarker signatures that manifest proportionate to the dose and severity of injury is crucial in expediting the discovery and development of novel and effective diagnostic, prognostic, and treatment approaches. Herein, we investigate and compare the response to high dose IR during the transition of bone\u2010derived mesenchymal stem cells to osteoblasts and adipocytes, macrophages to osteoclasts, and late osteoblasts to mature osteocytes in\u00a0vitro. Further, the counter response of bone to cumulative doses of 8, 16, and 24\u2009Gy was assessed in\u00a0vivo. Our findings indicate several novelties: cumulative radioresistance to DNA damage, apoptosis, reactive oxygen species formation, and dysfunctional mineral deposition was measured during osteoblast to osteocyte transition. Irradiation stimulated the formation of tunneling nanotube\u2010like structures, a novel type of intercellular communication machinery, in exposed macrophages. Bone fracture stress but not ultimate stress significantly decreased 48\u2009h after a single 8\u2009Gy exposure and prior to microarchitectural deterioration in\u00a0vivo. Thus, early frailty\u2010inducing micromechanisms may originate within the organic\/material component of bone independently of mechanical structure. Finally, data reveal dose\u2010 and severity\u2010related proteomic signatures of pathological toxicity. Engineered approaches that therapeutically target these fundamental cellular processes may offer a promising future strategy for the prevention and treatment of IR\u2010induced bone injury.<\/jats:p>","DOI":"10.1096\/fj.202600715rr","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T16:55:31Z","timestamp":1780073731000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Insights Into Dose\u2010Dependent Bone Toxicity Following Partial\u2010Body Exposure to Fractionated Ionizing Radiation In\u00a0Vivo"],"prefix":"10.1096","volume":"40","author":[{"given":"Fei","family":"Wei","sequence":"first","affiliation":[{"name":"Biionix Cluster, College of Medicine University of Central Florida  Orlando Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeda S.","family":"Jennifer","sequence":"additional","affiliation":[{"name":"Department of Industrial Engineering 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