Thomas Noonan

Background: Radiation therapy is an important part of cancer treatments; however, it often leaves bone with long term damage that is difficult to repair.  Patients develop associated bone loss, delays in the healing time of a fracture, and even osteoradionecrosis in regions previously irradiated. Current treatments focus on managing preexisting damage through pain control, rehabilitation, surgery, fracture stabilization and antibiotics.  While these interventions are certainly important, they do not address the underlying problem, irradiated bone loses regenerative capabilities.  Normal bone remodeling relies on a distinct balance between resorption of bone by osteoclasts with an associated formation by osteoblasts.  Radiation disrupts this balance and through injury of mesenchymal stem cells it increases oxidative stress, damages mitochondria, and pushes progenitor cells away from osteogenesis, instead promoting adipogenesis.  Wnt/β-catenin is a critical pathway to their process because activated β-catenin is directly associated with osteoblast differentiation and reinforced bone formation. ^1-5

Objective: This review examines the manners in which radiation-induced mesenchymal stem cell damage contributes to impaired bone repair and studies emerging therapies to restore osteogenesis.  These therapies target mitochondrial repair, inflammatory modulation, redox control, stem cell repair and Wnt/β-catenin activation.

Search Methods: A literature review was conducted using PubMed and Google Scholar to identify studies published from 2019-2025.  Search terms included “radiation-induced bone injury,” “mesenchymal stem cells,” “osteogenesis,” “Wnt beta-catenin,” “MSC-derived exosomes,” “osteoradionecrosis,” “irradiated bone repair,” “mitochondrial dysfunction,” and “dendritic cells.” Primary mechanistic and translational studies were identified and prioritized, while review articles were used to provide background on radiation-associated skeletal injury and extracellular vesicle-mediated bone regeneration.

Results: The literature reviewed supported the idea that radiation-induced bone injury is not purely a structural injury, but also a failure of the pathways needed for repair and regeneration.  Ren et al demonstrated that radiation persistently suppressed osteogenic markers while osteoclast activity rose in the immediate aftermath of radiation before eventually returning closer to baseline levels.  This suggests that the major problem is failure of osteoblasts, not just increased bone resorption.  Their study also identified a Ca²⁺–calcineurin–NFATc1–Fis1 pathway in which radiation caused mitochondrial damage, impaired oxidative phosphorylation, reduced ATP production, and decreased antioxidant defenses.  Therapeutic strategies involved the inhibition of Fis1 which was very significant because it subsequently partially restored osteogenesis and bone structure.¹  Zheng et al showed that radiation can also damage the surrounding bone marrow environment suppressing mesenchymal stem cell proliferation and osteogenic differentiation as a response to inflammatory signaling.²  Chen et al found evidence that taurine supplementation reduced reactive oxygen species and DNA damage while improving osteogenesis in irradiated bone marrow stromal cells.³ Zuo et al gave the clearest connection between exosome therapy and Wnt/β-catenin signaling. In mice, supplementation of bone marrow mesenchymal stem cell-derived exosomes improved trabecular bone structure, reduced oxidative stress, restored recipient mesenchymal stem cell function, decreased adipogenic markers, increased osteogenic markers, and increased β-catenin expression.⁴   Lynn et al further showed that stem-cell-based therapies can improve healing in irradiated mandibular fracture models, with adipose-derived stem cells improving vascular outcomes and rates of fracture repair.⁵

Conclusion: Radiation-induced bone injury is truly a problem of failed regeneration.  Radiation damages the stem cells responsible for bone formation, disrupts normal mitochondrial function, increases inflammation and oxidative stress all while suppressing osteogenic signaling.  The studies reviewed suggest that to successfully treat this issue clinicians will need to do far more than just stabilize the injured bone.  They will need to restore the biology behind healing bone.  Wnt/β-catenin signaling appears to be one important pathway involved in this recovery but there is still much to learn. Future research should focus on how these therapies can be safely translated into clinical practice particularly by finding optimal dosing, timing, and delivery methods for associated drugs.  It will also require research on the long-term safety, and whether combination strategies are needed for patients with radiation-induced skeletal injuries.

Works Cited

1. Ren L, Chen X, Zheng Y, Li J, Yu J, Ou L, Liu G, Cheng B, Toh WS, Xia J. Mitochondrial dysfunction in mesenchymal stem cells impairs osteogenesis in radiation-induced bone injury via Ca²⁺-NFATc1-Fis1 pathway. Cell Death Dis. 2025;17(1):69. doi:10.1038/s41419-025-08281-w
2. Zheng M, Chen H, Liu Z, Wang Z, Jiang T, He Y. Ionizing radiation-mediated dendritic cell maturation exacerbates inflammatory response of bone marrow mesenchymal stem cells and impairs osteogenesis in radiation-induced jaw injury. Stem Cell Res Ther. 2025;16(1):388. doi:10.1186/s13287-025-04508-x
3. Chen H, Zheng M, Li M, Zheng Y, Wang X, He Y. Taurine ameliorates radiation-induced oxidative stress in bone marrow mesenchymal stromal cells and promotes osteogenesis. Free Radic Biol Med. 2024;225:805-820. doi:10.1016/j.freeradbiomed.2024.10.308
4. Zuo R, Liu M, Wang Y, et al. BM-MSC-derived exosomes alleviate radiation-induced bone loss by restoring the function of recipient BM-MSCs and activating Wnt/β-catenin signaling. Stem Cell Res Ther. 2019;10(1):30. doi:10.1186/s13287-018-1121-9
5. Lynn JV, Ranganathan K, Luby AO, Urlaub KM, Donneys A, Nelson NS, Buchman SR. Therapeutic efficacy of adipose-derived stem cells versus bone marrow stromal cells for irradiated mandibular fracture repair. Ann Plast Surg. 2022;89(4):459-464. doi:10.1097/SAP.0000000000003301