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1
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Hughes-Fulford M, Carroll DJ, Allaway HCM, Dunbar BJ, Sawyer AJ. Women in space: A review of known physiological adaptations and health perspectives. Exp Physiol 2024. [PMID: 39487998 DOI: 10.1113/ep091527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 10/08/2024] [Indexed: 11/04/2024]
Abstract
Exposure to the spaceflight environment causes adaptations in most human physiological systems, many of which are thought to affect women differently from men. Since only 11.5% of astronauts worldwide have been female, these issues are largely understudied. The physiological nuances affecting the female body in the spaceflight environment remain inadequately defined since the last thorough published review on the subject. A PubMed literature search yielded over 2200 publications. Using NASA's 2014 review series 'The effects of sex and gender on adaptation to space' as a benchmark, we identified substantive advancements and persistent knowledge gaps in need of further study from the nearly 600 related articles that have been published since the initial review. This review highlights the most critical issues to mitigate medical risk and promote the success of missions to the Moon and Mars. Salient sex-linked differences observed terrestrially should be studied during upcoming missions, including increased levels of inflammatory markers, coagulation factors and leptin levels following sleep deprivation; correlation between body mass and the severity of spaceflight-associated neuro-ocular syndrome; increased incidence of orthostatic intolerance; increased severity of muscle atrophy and bone loss; differences in the incidence of urinary tract infections; and susceptibility to specific cancers after exposure to ionizing radiation. To optimize health and well-being among all astronauts, it is imperative to prioritize research that considers the physiological nuances of the female body. A more robust understanding of female physiology in the spaceflight environment will support crew readiness for Artemis missions and beyond.
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Affiliation(s)
- Millie Hughes-Fulford
- UC Space Health, University of California San Francisco (UCSF), San Francisco, California, USA
- Department of Medicine, UCSF, San Francisco, California, USA
| | - Danielle J Carroll
- UC Space Health, University of California San Francisco (UCSF), San Francisco, California, USA
- Department of Surgery, UCSF, San Francisco, California, USA
- Department of Bioastronautics, University of Colorado Boulder, Boulder, Colorado, USA
| | - Heather C M Allaway
- Department of Kinesiology, Texas A&M University, College Station, Texas, USA
- School of Kinesiology, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Bonnie J Dunbar
- Department of Aerospace Engineering, Texas A&M University, College Station, Texas, USA
- Texas A&M Engineering Experiment Station, Texas A&M University, College Station, Texas, USA
| | - Aenor J Sawyer
- UC Space Health, University of California San Francisco (UCSF), San Francisco, California, USA
- Department of Orthopaedic Surgery, UCSF, San Francisco, California, USA
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2
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Wu T, Bonnheim NB, Pendleton MM, Emerzian SR, Keaveny TM. Radiation-induced changes in load-sharing and structure-function behavior in murine lumbar vertebrae. Comput Methods Biomech Biomed Engin 2024; 27:1278-1286. [PMID: 37504955 DOI: 10.1080/10255842.2023.2239415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/12/2023] [Indexed: 07/29/2023]
Abstract
In this study, we used micro-CT-based finite element analysis to investigate the biomechanical effects of radiation on the microstructure and mechanical function of murine lumbar vertebrae. Specifically, we evaluated vertebral microstructure, whole-bone stiffness, and cortical-trabecular load sharing in the L5 vertebral body of mice exposed to ionizing radiation 11 days post exposure (5 Gy total dose; n = 13) and controls (n = 14). Our findings revealed the irradiated group exhibited reduced trabecular bone volume and microstructure (p < 0.001) compared to controls, while cortical bone volume remained unchanged (p = 0.91). Axially compressive loads in the irradiated group were diverted from the trabecular centrum and into the vertebral cortex, as evidenced by a higher cortical load-fraction (p = 0.02) and a higher proportion of cortical tissue at risk of initial failure (p < 0.01). Whole-bone stiffness was lower in the irradiated group compared to the controls, though the difference was small and non-significant (2045 ± 142 vs. 2185 ± 225 vs. N/mm, irradiated vs. control, p = 0.07). Additionally, the structure-function relationship between trabecular bone volume and trabecular load fraction differed between groups (p = 0.03), indicating a less biomechanically efficient trabecular network in the irradiated group. We conclude that radiation can decrease trabecular bone volume and result in a less biomechanically efficient trabecular structure, leading to increased reliance on the vertebral cortex to resist axially compressive loads. These findings offer biomechanical insight into the effects of radiation on structure-function behavior in murine lumbar vertebrae independent of possible tissue-level material effects.
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Affiliation(s)
- Tongge Wu
- Department of Mechanical Engineering, University of California, Berkeley, CA, USA
| | - Noah B Bonnheim
- Department of Orthopaedic Surgery, University of California, San Francisco, CA, USA
| | - Megan M Pendleton
- Department of Mechanical Engineering, University of California, Berkeley, CA, USA
| | - Shannon R Emerzian
- Department of Mechanical Engineering, University of California, Berkeley, CA, USA
| | - Tony M Keaveny
- Department of Mechanical Engineering, University of California, Berkeley, CA, USA
- Department of Bioengineering, University of California, Berkeley, CA, USA
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3
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Jullienne A, Malo M, Shaw K, Zheng Y, Johnston JD, Kontulainen S, Chilibeck PD, Dadachova E, Obenaus A, Sarty GE. Musculoskeletal perturbations of deep space radiation: Assessment using a Gateway MRI. LIFE SCIENCES IN SPACE RESEARCH 2024; 42:74-83. [PMID: 39067994 DOI: 10.1016/j.lssr.2024.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/25/2024] [Accepted: 05/27/2024] [Indexed: 07/30/2024]
Abstract
Human space exploration expansion from Low-Earth Orbit to deep space is accelerating the need to monitor and address the known health concerns related to deep space radiation. The human musculoskeletal system is vulnerable to these risks (alongside microgravity) and its health reflects the well-being of other body systems. Multiparametric magnetic resonance imaging (MRI) is an important approach for assessing temporal physiological changes in the musculoskeletal system. We propose that ultra-low-field MRI provides an optimal low Size Weight and Power (SwaP) solution for non-invasively monitoring muscle and bone changes on the planned Gateway lunar space station. Our proposed ultra-low-field Gateway MRI meets low SWaP design specifications mandated by limited room in the lunar space station. This review summarizes the current state of our knowledge on musculoskeletal consequences of spaceflight, especially with respect to radiation, and then elaborates how MRI can be used to monitor the deleterious effects of space travel and the efficacy of putative countermeasures. We argue that an ultra-low-field MRI in cis-lunar space on the Gateway can provide valuable research and medical insights into the effects of deep space radiation exposure on astronauts. Such an MRI would also allow the development of imaging protocols that would facilitate Earth-bound teams to monitor space personnel musculoskeletal changes during future interplanetary spaceflight. It will especially have a role in monitoring countermeasures, such as the use of melanin, in protecting space explorers.
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Affiliation(s)
- Amandine Jullienne
- School of Medicine, University of California Irvine, 1001 Health Sciences Rd, Irvine, CA 92617, United States
| | - Mackenzie Malo
- College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK S7N 5E5, Canada
| | - Keely Shaw
- College of Kinesiology, University of Saskatchewan, 87 Campus Dr, Saskatoon, SK S7N 5B2, Canada
| | - Yuwen Zheng
- College of Kinesiology, University of Saskatchewan, 87 Campus Dr, Saskatoon, SK S7N 5B2, Canada
| | - James D Johnston
- College of Engineering, University of Saskatchewan, 57 Campus Dr, Saskatoon, SK S7N 5A9, Canada
| | - Saija Kontulainen
- College of Kinesiology, University of Saskatchewan, 87 Campus Dr, Saskatoon, SK S7N 5B2, Canada
| | - Philip D Chilibeck
- College of Kinesiology, University of Saskatchewan, 87 Campus Dr, Saskatoon, SK S7N 5B2, Canada
| | - Ekaterina Dadachova
- College of Pharmacy and Nutrition, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK S7N 5E5, Canada
| | - Andre Obenaus
- School of Medicine, University of California Irvine, 1001 Health Sciences Rd, Irvine, CA 92617, United States; School of Medicine, University of California Riverside, United States
| | - Gordon E Sarty
- Space MRI Lab, University of Saskatchewan, QuanTA Centre, 9 Campus Dr, Saskatoon, SK S7N 5A5, Canada.
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4
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Jogdand A, Landolina M, Chen Y. Organs in orbit: how tissue chip technology benefits from microgravity, a perspective. FRONTIERS IN LAB ON A CHIP TECHNOLOGIES 2024; 3:1356688. [PMID: 38915901 PMCID: PMC11195915 DOI: 10.3389/frlct.2024.1356688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Tissue chips have become one of the most potent research tools in the biomedical field. In contrast to conventional research methods, such as 2D cell culture and animal models, tissue chips more directly represent human physiological systems. This allows researchers to study therapeutic outcomes to a high degree of similarity to actual human subjects. Additionally, as rocket technology has advanced and become more accessible, researchers are using the unique properties offered by microgravity to meet specific challenges of modeling tissues on Earth; these include large organoids with sophisticated structures and models to better study aging and disease. This perspective explores the manufacturing and research applications of microgravity tissue chip technology, specifically investigating the musculoskeletal, cardiovascular, and nervous systems.
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Affiliation(s)
- Aditi Jogdand
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, United States
| | - Maxwell Landolina
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, United States
| | - Yupeng Chen
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT, United States
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5
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Liu M, Lan Y, Qin Y, Gao Y, Deng Y, Li N, Zhang C, Ma H. Interaction between astrocytes and neurons in simulated space radiation-induced CNS injury. Int J Radiat Biol 2023; 99:1830-1840. [PMID: 37436484 DOI: 10.1080/09553002.2023.2232004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 05/26/2023] [Indexed: 07/13/2023]
Abstract
PURPOSE Astronauts exhibit neurological dysfunction during long-duration spaceflight, and the specific mechanisms may be closely related to the cumulative effects of these neurological injuries in the space radiation environment. Here, we investigated the interaction between astrocytes and neuronal cells exposed to simulated space radiation. MATERIALS AND METHODS we selected human astrocytes (U87 MG) and neuronal cells (SH-SY5Y) to establish an experimental model to explore the interaction between astrocytes and neuronal cells in the CNS under simulated space radiation environment and the role of exosomes in the interactions. RESULTS We found that γ-ray caused oxidative and inflammatory damage in human U87 MG and SH-SY5Y. The results of the conditioned medium transfer experiments showed that astrocytes exhibited a protective effect on neuronal cells, and neuronal cells influenced the activation of astrocytes in oxidative and inflammatory injury of CNS. We demonstrated that the number and size distribution of exosomes derived from U87 MG and SH-SY5Y cells were changed in response to H2O2, TNF-α or γ-ray treatment. Furthermore, we found that exosome derived from treated nerve cells influenced the cell viability and gene expression of untreated nerve cells, and the effect of exosomes was partly consistent with that of the conditioned medium. CONCLUSION Our findings demonstrated that astrocytes showed a protective effect on neuronal cells, and neuronal cells influenced the activation of astrocytes in oxidative and inflammatory damage of CNS induced by simulated space radiation. Exosomes played an essential role in the interaction between astrocytes and neuronal cells exposed to simulated space radiation.
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Affiliation(s)
- Mengjin Liu
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yu Lan
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yuhan Qin
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yanan Gao
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Yulin Deng
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Nuomin Li
- School of Medical Technology, Institute of Engineering Medicine, Beijing Institute of Technology, Beijing, China
| | - Chen Zhang
- School of Medical Technology, Institute of Engineering Medicine, Beijing Institute of Technology, Beijing, China
| | - Hong Ma
- School of Life Science, Beijing Institute of Technology, Beijing, China
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6
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Mammarella N, Gatti M, Ceccato I, Di Crosta A, Di Domenico A, Palumbo R. The Protective Role of Neurogenetic Components in Reducing Stress-Related Effects during Spaceflights: Evidence from the Age-Related Positive Memory Approach. LIFE (BASEL, SWITZERLAND) 2022; 12:life12081176. [PMID: 36013355 PMCID: PMC9410359 DOI: 10.3390/life12081176] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/22/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022]
Abstract
Fighting stress-related effects during spaceflight is crucial for a successful mission. Emotional, motivational, and cognitive mechanisms have already been shown to be involved in the decrease of negative emotions. However, emerging evidence is pointing to a neurogenetic profile that may render some individuals more prone than others to focusing on positive information in memory and increasing affective health. The relevance for adaptation to the space environment and the interaction with other stressors such as ionizing radiations is discussed. In particular, to clarify this approach better, we will draw from the psychology and aging literature data. Subsequently, we report on studies on candidate genes for sensitivity to positive memories. We review work on the following candidate genes that may be crucial in adaptation mechanisms: ADRA2B, COMT, 5HTTLPR, CB1, and TOMM40. The final aim is to show how the study of genetics and cell biology of positive memory can help us to reveal the underlying bottom-up pathways to also increasing positive effects during a space mission.
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Affiliation(s)
- Nicola Mammarella
- Department of Psychological Sciences, Health and Territory, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy; (M.G.); (A.D.C.); (A.D.D.); (R.P.)
- Correspondence:
| | - Matteo Gatti
- Department of Psychological Sciences, Health and Territory, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy; (M.G.); (A.D.C.); (A.D.D.); (R.P.)
| | - Irene Ceccato
- Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy;
| | - Adolfo Di Crosta
- Department of Psychological Sciences, Health and Territory, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy; (M.G.); (A.D.C.); (A.D.D.); (R.P.)
| | - Alberto Di Domenico
- Department of Psychological Sciences, Health and Territory, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy; (M.G.); (A.D.C.); (A.D.D.); (R.P.)
| | - Rocco Palumbo
- Department of Psychological Sciences, Health and Territory, University G. d’Annunzio of Chieti-Pescara, 66100 Chieti, Italy; (M.G.); (A.D.C.); (A.D.D.); (R.P.)
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7
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Eleutheroside E supplementation prevents radiation-induced cognitive impairment and activates PKA signaling via gut microbiota. Commun Biol 2022; 5:680. [PMID: 35804021 PMCID: PMC9270490 DOI: 10.1038/s42003-022-03602-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 05/04/2022] [Indexed: 11/08/2022] Open
Abstract
Radiation affects not only cognitive function but also gut microbiota. Eleutheroside E (EE), a principal active compound of Acanthopanax senticosus, has a certain protective effect on the nervous system. Here, we find a four-week EE supplementation to the 60Co-γ ray irradiated mice improves the cognition and spatial memory impairments along with the protection of hippocampal neurons, remodels the gut microbiota, especially changes of Lactobacillus and Helicobacter, and altered the microbial metabolites including neurotransmitters (GABA, NE, ACH, 5-HT) as well as their precursors. Furthermore, the fecal transplantation of EE donors verifies that EE alleviated cognition and spatial memory impairments, and activates the PKA/CREB/BDNF signaling via gut microbiota. Our findings provide insight into the mechanism of EE effect on the gut-brain axis and underpin a proposed therapeutic value of EE in cognitive and memory impairments induced by radiation.
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8
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Yin BF, Li ZL, Yan ZQ, Guo Z, Liang JW, Wang Q, Zhao ZD, Li PL, Hao RC, Han MY, Li XT, Mao N, Ding L, Chen DF, Gao Y, Zhu H. Psoralen alleviates radiation-induced bone injury by rescuing skeletal stem cell stemness through AKT-mediated upregulation of GSK-3β and NRF2. Stem Cell Res Ther 2022; 13:241. [PMID: 35672836 PMCID: PMC9172007 DOI: 10.1186/s13287-022-02911-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Repairing radiation-induced bone injuries remains a significant challenge in the clinic, and few effective medicines are currently available. Psoralen is a principal bioactive component of Cullen corylifolium (L.) Medik and has been reported to have antitumor, anti-inflammatory, and pro-osteogenesis activities. However, less information is available regarding the role of psoralen in the treatment of radiation-induced bone injury. In this study, we explored the modulatory effects of psoralen on skeletal stem cells and their protective effects on radiation-induced bone injuries. METHODS The protective effects of psoralen on radiation-induced osteoporosis and irradiated bone defects were evaluated by microCT and pathological analysis. In addition, the cell proliferation, osteogenesis, and self-renewal of SSCs were explored. Further, the underlying mechanisms of the protective of psoralen were investigated by using RNA sequencing and functional gain and loss experiments in vitro and in vivo. Statistical significance was analyzed using Student's t test. The one-way ANOVA was used in multiple group data analysis. RESULTS Here, we demonstrated that psoralen, a natural herbal extract, mitigated radiation-induced bone injury (irradiation-induced osteoporosis and irradiated bone defects) in mice partially by rescuing the stemness of irradiated skeletal stem cells. Mechanistically, psoralen restored the stemness of skeletal stem cells by alleviating the radiation-induced suppression of AKT/GSK-3β and elevating NRF2 expression in skeletal stem cells. Furthermore, the expression of KEAP1 in skeletal stem cells did not significantly change in the presence of psoralen. Moreover, blockade of NRF2 in vivo partially abolished the promising effects of psoralen in a murine model of irradiation-induced osteoporosis and irradiated bone regeneration. CONCLUSIONS In summary, our findings identified psoralen as a potential medicine to mitigate bone radiation injury. In addition, skeletal stem cells and AKT-GSK-3β and NRF2 may thus represent therapeutic targets for treating radiation-induced bone injury.
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Affiliation(s)
- Bo-Feng Yin
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Zhi-Ling Li
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Zi-Qiao Yan
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China
| | - Zheng Guo
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China.,Medical Center of Air Forces, PLA, Road Fucheng 30, Beijing, 100142, People's Republic of China
| | - Jia-Wu Liang
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China.,Medical Center of Air Forces, PLA, Road Fucheng 30, Beijing, 100142, People's Republic of China
| | - Qian Wang
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China.,Medical Center of Air Forces, PLA, Road Fucheng 30, Beijing, 100142, People's Republic of China
| | - Zhi-Dong Zhao
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China.,Medical Center of Air Forces, PLA, Road Fucheng 30, Beijing, 100142, People's Republic of China
| | - Pei-Lin Li
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Rui-Cong Hao
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,Graduate School of Anhui Medical University, 81 Meishan Road, Shushan Qu, Hefei, 230032, Anhui, People's Republic of China
| | - Meng-Yue Han
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.,Graduate School of Anhui Medical University, 81 Meishan Road, Shushan Qu, Hefei, 230032, Anhui, People's Republic of China
| | - Xiao-Tong Li
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Ning Mao
- Beijing Institute of Basic Medical Sciences, Road Taiping 27, Beijing, 100850, People's Republic of China
| | - Li Ding
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China. .,Medical Center of Air Forces, PLA, Road Fucheng 30, Beijing, 100142, People's Republic of China.
| | - Da-Fu Chen
- Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Eastern Street Xinjiekou 31, Beijing, 100035, China.
| | - Yue Gao
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.
| | - Heng Zhu
- Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China. .,Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China. .,Graduate School of Anhui Medical University, 81 Meishan Road, Shushan Qu, Hefei, 230032, Anhui, People's Republic of China. .,Beijing Institute of Basic Medical Sciences, Road Taiping 27, Beijing, 100850, People's Republic of China.
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9
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Kumar K, Datta K, Fornace AJ, Suman S. Total body proton and heavy-ion irradiation causes cellular senescence and promotes pro-osteoclastogenic activity in mouse bone marrow. Heliyon 2022; 8:e08691. [PMID: 35028468 PMCID: PMC8741516 DOI: 10.1016/j.heliyon.2021.e08691] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/01/2021] [Accepted: 12/27/2021] [Indexed: 12/12/2022] Open
Abstract
Low-LET photon radiation-induced persistent alterations in bone marrow (BM) cells are well documented in total-body irradiated (TBI) rodents and also among radiotherapy patients. However, the late effects of protons and high-LET heavy-ion radiation on BM cells and its implications in osteoclastogenesis are not fully understood. Therefore, C57BL6/J female mice (8 weeks; n = 10/group) were irradiated to sham, and 1 Gy of the proton (0.22 keV/μm), or high-LET 56Fe-ions (148 keV/μm) and at 60 d post-exposure, mice were sacrificed and femur sections were obtained for histological, cellular and molecular analysis. Cell proliferation (PCNA), cell death (active caspase-3), senescence (p16), osteoclast (RANK), osteoblast (OPG), osteoblast progenitor (c-Kit), and osteoclastogenesis-associated secretory factors (like RANKL) were assessed using immunostaining. While no change in cell proliferation and apoptosis between control and irradiated groups was noted, the number of BM megakaryocytes was significantly reduced in irradiated mice at 60 d post-exposure. A remarkable increase in p16 positive cells indicated a persistent increase in cell senescence, whereas increased RANKL/OPG ratio, reductions in the number of osteoblast progenitor cells, and osteocalcin provided clear evidence that exposure to both proton and 56Fe-ions promotes pro-osteoclastogenic activity in BM. Among irradiated groups, 56Fe-induced alterations in the BM cellularity and osteoclastogenesis were significantly greater than the protons that demonstrated a radiation quality-dependent effect. This study has implications in understanding the role of IR-induced late changes in the BM cells and its involvement in bone degeneration among deep-space astronauts, and also in patients undergoing proton or heavy-ion radiotherapy.
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Affiliation(s)
- Kamendra Kumar
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Kamal Datta
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Albert J. Fornace
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Shubhankar Suman
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Corresponding author.
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10
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Pendleton MM, Emerzian SR, Sadoughi S, Li A, Liu JW, Tang SY, O'Connell GD, Sibonga JD, Alwood JS, Keaveny TM. Relations Between Bone Quantity, Microarchitecture, and Collagen Cross-links on Mechanics Following In Vivo Irradiation in Mice. JBMR Plus 2021; 5:e10545. [PMID: 34761148 PMCID: PMC8567491 DOI: 10.1002/jbm4.10545] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 08/20/2021] [Indexed: 01/22/2023] Open
Abstract
Humans are exposed to ionizing radiation via spaceflight or cancer radiotherapy, and exposure from radiotherapy is known to increase risk of skeletal fractures. Although irradiation can reduce trabecular bone mass, alter trabecular microarchitecture, and increase collagen cross‐linking, the relative contributions of these effects to any loss of mechanical integrity remain unclear. To provide insight, while addressing both the monotonic strength and cyclic‐loading fatigue life, we conducted total‐body, acute, gamma‐irradiation experiments on skeletally mature (17‐week‐old) C57BL/6J male mice (n = 84). Mice were administered doses of either 0 Gy (sham), 1 Gy (motivated by cumulative exposures from a Mars mission), or 5 Gy (motivated by clinical therapy regimens) with retrieval of the lumbar vertebrae at either a short‐term (11‐day) or long‐term (12‐week) time point after exposure. Micro‐computed tomography was used to assess trabecular and cortical quantity and architecture, biochemical composition assays were used to assess collagen quality, and mechanical testing was performed to evaluate vertebral compressive strength and fatigue life. At 11 days post‐exposure, 5 Gy irradiation significantly reduced trabecular mass (p < 0.001), altered microarchitecture (eg, connectivity density p < 0.001), and increased collagen cross‐links (p < 0.001). Despite these changes, vertebral strength (p = 0.745) and fatigue life (p = 0.332) remained unaltered. At 12 weeks after 5 Gy exposure, the trends in trabecular bone persisted; in addition, regardless of irradiation, cortical thickness (p < 0.01) and fatigue life (p < 0.01) decreased. These results demonstrate that the highly significant effects of 5 Gy total‐body irradiation on the trabecular bone morphology and collagen cross‐links did not translate into detectable effects on vertebral mechanics. The only mechanical deficits observed were associated with aging. Together, these vertebral results suggest that for spaceflight, irradiation alone will likely not alter failure properties, and for radiotherapy, more investigations that include post‐exposure time as a positive control and testing of both failure modalities are needed to determine the cause of increased fracture risk. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
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Affiliation(s)
- Megan M Pendleton
- Department of Mechanical Engineering University of California Berkeley CA USA
| | - Shannon R Emerzian
- Department of Mechanical Engineering University of California Berkeley CA USA
| | - Saghi Sadoughi
- Department of Mechanical Engineering University of California Berkeley CA USA
| | - Alfred Li
- Endocrine Research Unit University of California and Veteran Affairs Medical Center San Francisco CA USA
| | - Jennifer W Liu
- Department of Orthopaedic Surgery Washington University St. Louis MO USA
| | - Simon Y Tang
- Department of Orthopaedic Surgery Washington University St. Louis MO USA.,Department of Biomedical Engineering Washington University St. Louis MO USA.,Department of Mechanical Engineering and Materials Science Washington University St. Louis MO USA
| | - Grace D O'Connell
- Department of Mechanical Engineering University of California Berkeley CA USA.,Department of Orthopaedic Surgery University of California San Francisco CA USA
| | - Jean D Sibonga
- Biomedical Research and Environmental Sciences Division NASA Johnson Space Center Houston TX USA
| | - Joshua S Alwood
- Space Biosciences Division NASA Ames Research Center Moffett Field CA USA
| | - Tony M Keaveny
- Department of Mechanical Engineering University of California Berkeley CA USA.,Department of Bioengineering University of California Berkeley CA USA
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11
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Kim HN, Richardson KK, Krager KJ, Ling W, Simmons P, Allen AR, Aykin-Burns N. Simulated Galactic Cosmic Rays Modify Mitochondrial Metabolism in Osteoclasts, Increase Osteoclastogenesis and Cause Trabecular Bone Loss in Mice. Int J Mol Sci 2021; 22:11711. [PMID: 34769141 PMCID: PMC8583929 DOI: 10.3390/ijms222111711] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/18/2021] [Accepted: 10/19/2021] [Indexed: 11/24/2022] Open
Abstract
Space is a high-stress environment. One major risk factor for the astronauts when they leave the Earth's magnetic field is exposure to ionizing radiation from galactic cosmic rays (GCR). Several adverse changes occur in mammalian anatomy and physiology in space, including bone loss. In this study, we assessed the effects of simplified GCR exposure on skeletal health in vivo. Three months following exposure to 0.5 Gy total body simulated GCR, blood, bone marrow and tissue were collected from 9 months old male mice. The key findings from our cell and tissue analysis are (1) GCR induced femoral trabecular bone loss in adult mice but had no effect on spinal trabecular bone. (2) GCR increased circulating osteoclast differentiation markers and osteoclast formation but did not alter new bone formation or osteoblast differentiation. (3) Steady-state levels of mitochondrial reactive oxygen species, mitochondrial and non-mitochondrial respiration were increased without any changes in mitochondrial mass in pre-osteoclasts after GCR exposure. (4) Alterations in substrate utilization following GCR exposure in pre-osteoclasts suggested a metabolic rewiring of mitochondria. Taken together, targeting radiation-mediated mitochondrial metabolic reprogramming of osteoclasts could be speculated as a viable therapeutic strategy for space travel induced bone loss.
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Affiliation(s)
- Ha-Neui Kim
- Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (K.K.R.); (W.L.)
| | - Kimberly K. Richardson
- Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (K.K.R.); (W.L.)
| | - Kimberly J. Krager
- Department of Pharmaceutical Sciences, Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (K.J.K.); (P.S.); (A.R.A.)
| | - Wen Ling
- Center for Musculoskeletal Disease Research and Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (K.K.R.); (W.L.)
| | - Pilar Simmons
- Department of Pharmaceutical Sciences, Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (K.J.K.); (P.S.); (A.R.A.)
| | - Antino R. Allen
- Department of Pharmaceutical Sciences, Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (K.J.K.); (P.S.); (A.R.A.)
| | - Nukhet Aykin-Burns
- Department of Pharmaceutical Sciences, Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA; (K.J.K.); (P.S.); (A.R.A.)
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12
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Li Z, MacDougald OA. Preclinical models for investigating how bone marrow adipocytes influence bone and hematopoietic cellularity. Best Pract Res Clin Endocrinol Metab 2021; 35:101547. [PMID: 34016532 PMCID: PMC8458229 DOI: 10.1016/j.beem.2021.101547] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Laboratory mice are a crucial preclinical model system for investigating bone marrow adipocyte (BMAd)-bone and BMAd-hematopoiesis interactions. In this review, we evaluate the suitability of mice to model common human diseases related to osteopenia or hematopoietic disorders, point out consistencies and discrepancies among different studies, and provide insights into model selection. Species, age, sex, skeletal site, and treatment protocol should all be considered when designing future studies.
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Affiliation(s)
- Ziru Li
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ormond A MacDougald
- Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
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13
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Dahl M, Smith EM, Warsi S, Rothe M, Ferraz MJ, Aerts JM, Golipour A, Harper C, Pfeifer R, Pizzurro D, Schambach A, Mason C, Karlsson S. Correction of pathology in mice displaying Gaucher disease type 1 by a clinically-applicable lentiviral vector. Mol Ther Methods Clin Dev 2021; 20:312-323. [PMID: 33511245 PMCID: PMC7806948 DOI: 10.1016/j.omtm.2020.11.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/28/2020] [Indexed: 12/02/2022]
Abstract
Gaucher disease type 1 (GD1) is an inherited lysosomal disorder with multisystemic effects in patients. Hallmark symptoms include hepatosplenomegaly, cytopenias, and bone disease with varying degrees of severity. Mutations in a single gene, glucosidase beta acid 1 (GBA1), are the underlying cause for the disorder, resulting in insufficient activity of the enzyme glucocerebrosidase, which in turn leads to a progressive accumulation of the lipid component glucocerebroside. In this study, we treat mice with signs consistent with GD1, with hematopoietic stem/progenitor cells transduced with a lentiviral vector containing an RNA transcript that, after reverse transcription, results in codon-optimized cDNA that, upon its integration into the genome encodes for functional human glucocerebrosidase. Five months after gene transfer, a highly significant reduction in glucocerebroside accumulation with subsequent reversal of hepatosplenomegaly, restoration of blood parameters, and a tendency of increased bone mass and density was evident in vector-treated mice compared to non-treated controls. Furthermore, histopathology revealed a prominent reduction of Gaucher cell infiltration after gene therapy. The vector displayed an oligoclonal distribution pattern but with no sign of vector-induced clonal dominance and a typical lentiviral vector integration profile. Cumulatively, our findings support the initiation of the first clinical trial for GD1 using the lentiviral vector described here.
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Affiliation(s)
- Maria Dahl
- Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
| | - Emma M.K. Smith
- Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
| | - Sarah Warsi
- Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
| | - Michael Rothe
- Hannover Medical School, Institute of Experimental Hematology, Hannover, Germany
| | - Maria J. Ferraz
- Department of Medical Biochemistry, Leiden University, Leiden, the Netherlands
| | | | | | | | | | | | - Axel Schambach
- Hannover Medical School, Institute of Experimental Hematology, Hannover, Germany
- Division of Hematology/Oncology, Boston’s Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Chris Mason
- AVROBIO, Inc., Cambridge, MA, USA
- University College London, Advanced Centre for Biochemical Engineering, London, UK
| | - Stefan Karlsson
- Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden
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14
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Abd Rabou MA. Effect of Bone Marrow Transplantation on the Fetal Skeleton of Maternally Irradiated Pregnant Rats. Pak J Biol Sci 2021; 24:207-218. [PMID: 33683050 DOI: 10.3923/pjbs.2021.207.218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND OBJECTIVE Prenatal exposure to ionizing radiation can interfere with embryonic and fetal growth depending on the dose and gestational age. The present study was completed to evaluate the effect of transplanted bone marrow on the fetal skeleton of pregnant rats exposed to gamma radiation. MATERIALS AND METHODS Experimental animals were separated into 5 groups: C group, R7 group, R7+BM group, R14 group and R14+BM group. All pregnant rats were sacrificed on day 20 days of gestation and the skeletal systems of the fetuses were examined and photographed. This study focused on skull, upper and lower jaw, occipital region, sacral and caudal region, fore and hind limbs. RESULTS Gamma rays caused any disturbance in the ossification process of the skull bones, upper and lower jaws, occipital bones, it caused the loss of some ossification centers in metacarpal bones, metatarsal bones but bone marrow transplantation greatly reduced the injury that happened because of γ-radiation. CONCLUSION This study showed that transplantation of bone marrow post-irradiation in pregnant rats could reduce the hazards of gamma-irradiation in the different regions of the fetal skeleton.
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15
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Little-Letsinger SE, Turner ND, Ford JR, Suva LJ, Bloomfield SA. Omega-3 fatty acid modulation of serum and osteocyte tumor necrosis factor-α in adult mice exposed to ionizing radiation. J Appl Physiol (1985) 2021; 130:627-639. [PMID: 33411639 DOI: 10.1152/japplphysiol.00848.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Chronic inflammation leads to bone loss and fragility. Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) consistently promote bone resorption. Dietary modulation of proinflammatory cytokines is an accepted therapeutic approach to treat chronic inflammation, including that induced by space-relevant radiation exposure. As such, these studies were designed to determine whether an anti-inflammatory diet, high in omega-3 fatty acids, could reduce radiation-mediated bone damage via reductions in the levels of inflammatory cytokines in osteocytes and serum. Lgr5-EGFP C57BL/6 mice were randomized to receive diets containing fish oil and pectin (FOP; high in omega-3 fatty acids) or corn oil and cellulose (COC; high in omega-6 fatty acids) and then acutely exposed to 0.5-Gy 56Fe or 2.0-Gy gamma-radiation. Mice fed the FOP diet exhibited consistent reductions in serum TNF-α in the 56Fe experiment but not the gamma-experiment. The percentage osteocytes (%Ot) positive for TNF-α increased in gamma-exposed COC, but not FOP, mice. Minimal changes in %Ot positive for sclerostin were observed. FOP mice exhibited modest improvements in several measures of cancellous microarchitecture and volumetric bone mineral density (BMD) postexposure to 56Fe and gamma-radiation. Reduced serum TNF-α in FOP mice exposed to 56Fe was associated with either neutral or modestly positive changes in bone structural integrity. Collectively, these data are generally consistent with previous findings that dietary intake of omega-3 fatty acids may effectively mitigate systemic inflammation after acute radiation exposure and facilitate maintenance of BMD during spaceflight in humans.NEW & NOTEWORTHY This is the first investigation, to our knowledge, to test the impact of a diet high in omega-3 fatty acids on multiple bone structural and biological outcomes following space-relevant radiation exposure. Novel in biological outcomes is the assessment of osteocyte responses to this stressor. These data also add to the growing evidence that low-dose exposures to even high-energy ion species like 56Fe may have neutral or even small positive impacts on bone.
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Affiliation(s)
| | - Nancy D Turner
- Nutrition and Food Sciences, Texas A&M University, College Station, Texas
| | - John R Ford
- Nuclear Engineering, Texas A&M University, College Station, Texas
| | - Larry J Suva
- Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Susan A Bloomfield
- Departments of Health and Kinesiology, Texas A&M University, College Station, Texas
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16
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Willey JS, Britten RA, Blaber E, Tahimic CG, Chancellor J, Mortreux M, Sanford LD, Kubik AJ, Delp MD, Mao XW. The individual and combined effects of spaceflight radiation and microgravity on biologic systems and functional outcomes. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, TOXICOLOGY AND CARCINOGENESIS 2021; 39:129-179. [PMID: 33902391 PMCID: PMC8274610 DOI: 10.1080/26896583.2021.1885283] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Both microgravity and radiation exposure in the spaceflight environment have been identified as hazards to astronaut health and performance. Substantial study has been focused on understanding the biology and risks associated with prolonged exposure to microgravity, and the hazards presented by radiation from galactic cosmic rays (GCR) and solar particle events (SPEs) outside of low earth orbit (LEO). To date, the majority of the ground-based analogues (e.g., rodent or cell culture studies) that investigate the biology of and risks associated with spaceflight hazards will focus on an individual hazard in isolation. However, astronauts will face these challenges simultaneously Combined hazard studies are necessary for understanding the risks astronauts face as they travel outside of LEO, and are also critical for countermeasure development. The focus of this review is to describe biologic and functional outcomes from ground-based analogue models for microgravity and radiation, specifically highlighting the combined effects of radiation and reduced weight-bearing from rodent ground-based tail suspension via hind limb unloading (HLU) and partial weight-bearing (PWB) models, although in vitro and spaceflight results are discussed as appropriate. The review focuses on the skeletal, ocular, central nervous system (CNS), cardiovascular, and stem cells responses.
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Affiliation(s)
| | | | - Elizabeth Blaber
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute
| | | | | | - Marie Mortreux
- Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center
| | - Larry D. Sanford
- Department of Radiation Oncology, Eastern Virginia Medical School
| | - Angela J. Kubik
- Department of Biomedical Engineering, Rensselaer Polytechnic Institute
| | - Michael D. Delp
- Department of Nutrition, Food and Exercise Sciences, Florida State University
| | - Xiao Wen Mao
- Division of Biomedical Engineering Sciences (BMES), Department of Basic Sciences, Loma Linda University
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17
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Suman S, Jaruga P, Dizdaroglu M, Fornace AJ, Datta K. Heavy ion space radiation triggers ongoing DNA base damage by downregulating DNA repair pathways. LIFE SCIENCES IN SPACE RESEARCH 2020; 27:27-32. [PMID: 34756227 DOI: 10.1016/j.lssr.2020.07.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/03/2020] [Accepted: 07/05/2020] [Indexed: 06/13/2023]
Abstract
Long-duration space missions outside low earth orbit will expose astronauts to a cumulative dose of high-energy particle radiation especially to highly damaging heavy ion radiation, which poses considerable risk to astronauts' health. The purpose of the current study was to quantitatively identify oxidatively induced DNA base modifications and assess status of the repair pathways involved in removing the modified bases in mouse intestinal cells after exposure to γ-rays and iron radiation. Mice (C57BL/6J; 6 to 8 weeks; female) were exposed to 0.5 Gy of either γ-rays or iron radiation and control mice were sham-irradiated. Intestinal tissues were collected 2 months after radiation. DNA base lesions were measured using gas chromatography-tandem mass spectrometry with isotope‑dilution. Base excision repair (BER) and nucleotide excision repair (NER) pathways were assessed using PCR and immunoblotting. Effects of iron radiation were compared to γ-rays and sham-irradiated controls. Exposure to iron radiation resulted in significantly higher levels of several DNA base lesions relative to control animals and those exposed to γ radiation. Assessment of BER and NER showed downregulation of pathway factors both at the RNA as well as at the protein levels. Our results not only provide important insight into DNA damage pattern in intestinal cells in response to iron radiation, but they also confirm our previous immunohistochemistry data on oxidatively induced DNA damage. We suggest that downregulation of the BER and NER pathways is contributing to ongoing DNA base damages long time after radiation exposure and has implications for chronic diseases including gastrointestinal diseases after heavy ion radiation exposure during space travel.
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Affiliation(s)
- Shubhankar Suman
- Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Research Building, Room E518, 3970 Reservoir Rd., NW, Washington, DC 20057, USA
| | - Pawel Jaruga
- Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA
| | - Miral Dizdaroglu
- Biomolecular Measurement Division, National Institute of Standards and Technology, Gaithersburg, MD 20899, USA
| | - Albert J Fornace
- Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Research Building, Room E518, 3970 Reservoir Rd., NW, Washington, DC 20057, USA
| | - Kamal Datta
- Department of Biochemistry and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University, Research Building, Room E518, 3970 Reservoir Rd., NW, Washington, DC 20057, USA.
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18
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The Influence of Radiation on Bone and Bone Cells-Differential Effects on Osteoclasts and Osteoblasts. Int J Mol Sci 2020; 21:ijms21176377. [PMID: 32887421 PMCID: PMC7504528 DOI: 10.3390/ijms21176377] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/31/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023] Open
Abstract
The bone is a complex organ that is dependent on a tight regulation between bone formation by osteoblasts (OBs) and bone resorption by osteoclasts (OCs). These processes can be influenced by environmental factors such as ionizing radiation (IR). In cancer therapy, IR is applied in high doses, leading to detrimental effects on bone, whereas radiation therapy with low doses of IR is applied for chronic degenerative and inflammatory diseases, with a positive impact especially on bone homeostasis. Moreover, the effects of IR are of particular interest in space travel, as astronauts suffer from bone loss due to space radiation and microgravity. This review summarizes the current state of knowledge on the effects of IR on bone with a special focus on the influence on OCs and OBs, as these cells are essential in bone remodeling. In addition, the influence of IR on the bone microenvironment is discussed. In summary, the effects of IR on bone and bone remodeling cells strongly depend on the applied radiation dose, as differential results are provided from in vivo as well as in vitro studies with varying doses of IR. Furthermore, the isolated effects of IR on a single cell type are difficult to determine, as the bone cells and bone microenvironment are building a tightly regulated network, influencing on one another. Therefore, future research is necessary in order to elucidate the influence of different bone cells on the overall radiation-induced effects on bone.
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19
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Seo MH, Lee MY, Eo MY, Lee SK, Woo KM, Kim SM. Development of a standardized mucositis and osteoradionecrosis animal model using external radiation. J Korean Assoc Oral Maxillofac Surg 2020; 46:240-249. [PMID: 32855371 PMCID: PMC7469963 DOI: 10.5125/jkaoms.2020.46.4.240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/13/2019] [Accepted: 09/16/2019] [Indexed: 11/25/2022] Open
Abstract
Objectives Although the side effects of radiation therapy vary from mucositis to osteomyelitis depending on the dose of radiation therapy, to date, an experimental animal model has not yet been proposed. The aim of this study was to develop an animal model for assessing complications of irradiated bone, especially to quantify the dose of radiation needed to develop a rat model. Materials and Methods Sixteen Sprague-Dawley rats aged seven weeks with a mean weight of 267.59 g were used. Atraumatic extraction of a right mandibular first molar was performed. At one week after the extraction, the rats were randomized into four groups and received a single dose of external radiation administered to the right lower jaw at a level of 14, 16, 18, or 20 Gy, respectively. Clinical alopecia with body weight changes were compared and bony volumetric analysis with micro-computed tomography (CT), histologic analysis with H&E were performed. Results The progression of the skin alopecia was different depending on the irradiation dose. Micro-CT parameters including bone volume, bone volume/tissue volume, bone mineral density, and trabecular spaces, showed no significant differences. The progression of osteoradionecrosis (ORN) along with that of inflammation, fibrosis, and bone resorption, was found with increased osteoclast or fibrosis in the radiated group. As the radiation dose increases, osteoclast numbers begin to decrease and osteoclast tends to increase. Osteoclasts respond more sensitively to the radiation dose, and osteoblasts are degraded at doses above 18 Gy. Conclusion A standardized animal model clinically comparable to ORN of the jaw is a valuable tool that can be used to examine the pathophysiology of the disease and trial any potential treatment modalities. We present a methodology for the use of an experimental rat model that incorporates a guideline regarding radiation dose.
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Affiliation(s)
- Mi Hyun Seo
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
| | - Min Young Lee
- Laboratory Animal Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
| | - Mi Young Eo
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
| | - Suk Keun Lee
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea
| | - Kyung Mi Woo
- Department of Pharmacology & Dental Therapeutics, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
| | - Soung Min Kim
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea
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20
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Siddiqui R, Akbar N, Khan NA. Gut microbiome and human health under the space environment. J Appl Microbiol 2020; 130:14-24. [PMID: 32692438 DOI: 10.1111/jam.14789] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 07/10/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022]
Abstract
The gut microbiome is well recognized to have a pivotal role in regulation of the health and behaviour of the host, affecting digestion, metabolism, immunity, and has been linked to changes in bones, muscles and the brain, to name a few. However, the impact of microgravity environment on gut bacteria is not well understood. In space environments, astronauts face several health issues including stress, high iron diet, radiation and being in a closed system during extended space missions. Herein, we discuss the role of gut bacteria in the space environment, in relation to factors such as microgravity, radiation and diet. Gut bacteria may exact their effects by synthesis of molecules, their absorption, and through physiological effects on the host. Moreover we deliberate the role of these challenges in the dysbiosis of the human microbiota and possible dysregulation of the immune system.
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Affiliation(s)
- R Siddiqui
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, University City, Sharjah, United Arab Emirates
| | - N Akbar
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, University City, Sharjah, United Arab Emirates
| | - N A Khan
- Department of Biology, Chemistry and Environmental Sciences, College of Arts and Sciences, American University of Sharjah, University City, Sharjah, United Arab Emirates
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21
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Chandra A, Lagnado AB, Farr JN, Monroe DG, Park S, Hachfeld C, Tchkonia T, Kirkland JL, Khosla S, Passos JF, Pignolo RJ. Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss. J Bone Miner Res 2020; 35:1119-1131. [PMID: 32023351 PMCID: PMC7357625 DOI: 10.1002/jbmr.3978] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 01/18/2020] [Accepted: 01/29/2020] [Indexed: 12/11/2022]
Abstract
Clinical radiotherapy treats life-threatening cancers, but the radiation often affects neighboring normal tissues including bone. Acute effects of ionizing radiation include oxidative stress, DNA damage, and cellular apoptosis. We show in this study that a large proportion of bone marrow cells, osteoblasts, and matrix-embedded osteocytes recover from these insults only to attain a senescent profile. Bone analyses of senescence-associated genes, senescence-associated beta-galactosidase (SA-β-gal) activity, and presence of telomere dysfunction-induced foci (TIF) at 1, 7, 14, 21, and 42 days post-focal radiation treatment (FRT) in C57BL/6 male mice confirmed the development of senescent cells and the senescence-associated secretory phenotype (SASP). Accumulation of senescent cells and SASP markers were correlated with a significant reduction in bone architecture at 42 days post-FRT. To test if senolytic drugs, which clear senescent cells, alleviate FRT-related bone damage, we administered the senolytic agents, dasatinib (D), quercetin (Q), fisetin (F), and a cocktail of D and Q (D+Q). We found moderate alleviation of radiation-induced bone damage with D and Q as stand-alone compounds, but no such improvement was seen with F. However, the senolytic cocktail of D+Q reduced senescent cell burden as assessed by TIF+ osteoblasts and osteocytes, markers of senescence (p16 Ink4a and p21), and key SASP factors, resulting in significant recovery in the bone architecture of radiated femurs. In summary, this study provides proof of concept that senescent cells play a role in radiotherapy-associated bone damage, and that reduction in senescent cell burden by senolytic agents is a potential therapeutic option for alleviating radiotherapy-related bone deterioration. © 2020 American Society for Bone and Mineral Research.
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Affiliation(s)
- Abhishek Chandra
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA.,Department of Medicine, Division of Geriatric Medicine and Gerontology, Mayo Clinic College of Medicine, Rochester, MN, USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Anthony B Lagnado
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Joshua N Farr
- Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA.,Division of Endocrinology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - David G Monroe
- Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA.,Division of Endocrinology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Sean Park
- Department of Radiation Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Christine Hachfeld
- Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Tamar Tchkonia
- Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - James L Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA.,Department of Medicine, Division of Geriatric Medicine and Gerontology, Mayo Clinic College of Medicine, Rochester, MN, USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Sundeep Khosla
- Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA.,Division of Endocrinology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - João F Passos
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA.,Department of Medicine, Division of Geriatric Medicine and Gerontology, Mayo Clinic College of Medicine, Rochester, MN, USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Robert J Pignolo
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN, USA.,Department of Medicine, Division of Geriatric Medicine and Gerontology, Mayo Clinic College of Medicine, Rochester, MN, USA.,Robert and Arlene Kogod Center on Aging, Mayo Clinic College of Medicine, Rochester, MN, USA.,Division of Endocrinology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
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22
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Song C, Gao X, Song W, Zeng D, Shan S, Yin Y, Li Y, Baranenko D, Lu W. Simulated spatial radiation impacts learning and memory ability with alterations of neuromorphology and gut microbiota in mice. RSC Adv 2020; 10:16196-16208. [PMID: 35493686 PMCID: PMC9052872 DOI: 10.1039/d0ra01017k] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/01/2020] [Indexed: 12/26/2022] Open
Abstract
Complex space environments, including microgravity and radiation, affect the body's central nervous system, endocrine system, circulatory system, and reproductive system. Radiation-induced aberration in the neuronal integrity and cognitive functions are particularly well known. Moreover, ionizing radiation is a likely contributor to alterations in the microbiome. However, there is a lacuna between radiation-induced memory impairment and gut microbiota. The present study was aimed at investigating the effects of simulated space-type radiation on learning and memory ability and gut microbiota in mice. Adult mice were irradiated by 60Co-γ rays at 4 Gy to simulate spatial radiation; behavioral experiments, pathological experiments, and transmission electron microscopy all showed that radiation impaired learning and memory ability and hippocampal neurons in mice, which was similar to the cognitive impairment in neurodegenerative diseases. In addition, we observed that radiation destroyed the colonic structure of mice, decreased the expression of tight junction proteins, and increased inflammation levels, which might lead to dysregulation of the intestinal microbiota. We found a correlation between the brain and colon in the changes in neurotransmitters associated with learning and memory. The 16S rRNA results showed that the bacteria associated with these neurotransmitters were also changed at the genus level and were significantly correlated. These results indicate that radiation-induced memory and cognitive impairment can be linked to gut microbiota through neurotransmitters.
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Affiliation(s)
- Chen Song
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Xin Gao
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Wei Song
- College of Food Science and Technology, Northwest University Xi'an 710069 China
- Laboratory of Nutritional and Healthy Food-Individuation Manufacturing Engineering Xi'an 710069 Shanxi China
| | - Deyong Zeng
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Shan Shan
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Yishu Yin
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
| | - Yongzhi Li
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- China Astronaut Research and Training Centre Beijing China
| | - Denis Baranenko
- Biotechnologies of the Third Millennium, ITMO University Saint-Petersburg Russia
| | - Weihong Lu
- Institute of Extreme Environment Nutrition and Protection, Harbin Institute of Technology Harbin China
- National Local Joint Laboratory of Extreme Environmental Nutritional Molecule Synthesis Transformation and Separation Harbin China
- School of Chemistry and Chemical Engineering, Harbin Institute of Technology Harbin China
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23
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Suman S, Kallakury BVS, Fornace AJ, Datta K. Fractionated and Acute Proton Radiation Show Differential Intestinal Tumorigenesis and DNA Damage and Repair Pathway Response in Apc Min/+ Mice. Int J Radiat Oncol Biol Phys 2019; 105:525-536. [PMID: 31271826 DOI: 10.1016/j.ijrobp.2019.06.2532] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 05/08/2019] [Accepted: 06/24/2019] [Indexed: 11/26/2022]
Abstract
PURPOSE Proton radiation is a major component of the radiation field in outer space and is used clinically in radiation therapy of resistant cancers. Although epidemiologic studies in atom bomb survivors and radiologic workers have established radiation as a risk factor for colorectal cancer (CRC), we have yet to determine the risk of CRC posed by proton radiation owing to a lack of sufficient human or animal data. The purpose of the current study was to quantitatively and qualitatively characterize differential effects of acute and fractionated high-energy protons on colorectal carcinogenesis. METHODS AND MATERIALS We used ApcMin/+ mice, a well-studied CRC model, to examine acute versus fractionated proton radiation-induced differences in intestinal tumorigenesis and associated signaling pathways. Mice were exposed to 1.88 Gy of proton radiation delivered in a single fraction or in 4 equal daily fractions (0.47 Gy × 4). Intestinal tumor number and grade were scored 100 to 110 days after irradiation, and tumor and tumor-adjacent normal tissues were harvested to assess proliferative β-catenin/Akt pathways and DNA damage response and repair pathways relevant to colorectal carcinogenesis. RESULTS Significantly higher intestinal tumor number and grade, along with decreased differentiation, were observed after acute radiation relative to fractionated radiation. Acute protons induced upregulation of β-catenin and Akt pathways with increased proliferative marker phospho-histone H3. Increased DNA damage along with decreased DNA repair factors involved in mismatch repair and nonhomologous end joining were also observed after exposure to acute protons. CONCLUSIONS We show increased γH2AX, 53BP1, and 8-oxo-dG, suggesting that increased ongoing DNA damage along with decreased DNA repair factors and increased proliferative responses could be triggering a higher number of intestinal tumors after acute relative to fractionated proton exposures in ApcMin/+ mice. Taken together, our data suggest greater carcinogenic potential of acute relative to fractionated proton radiation.
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Affiliation(s)
- Shubhankar Suman
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC; Department of Oncology, Georgetown University Medical Center, Washington, DC
| | | | - Albert J Fornace
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC; Department of Oncology, Georgetown University Medical Center, Washington, DC
| | - Kamal Datta
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC; Department of Oncology, Georgetown University Medical Center, Washington, DC; Department of Pathology, Georgetown University Medical Center, Washington, DC.
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24
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Johnson D, Lawrence SE, Livingston EW, Hienz RD, Davis CM, Lau AG. Modeling Space Radiation Induced Bone Changes in Rat Femurs through Finite Element Analysis. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2019; 2018:1763-1766. [PMID: 30440736 DOI: 10.1109/embc.2018.8512620] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
As the duration of manned missions outside of the Earth's protective shielding increase, astronauts are at risk for exposure to space radiation. Various organ systems may be damaged due to exposure. This study investigates the bone strength changes using finite element modeling of Long Evans rats (n=85) subjected to graded, head-only proton (0, 10, 25, and 100 cGy, 150 MeV/n) and 28silicon (0, 10, 25, and 50 cGy, 300 MeV/n) radiation. The strength of the femoral neck will be examined due its clinical relevance to hip fractures. It has been shown in previous studies that bone mineral density was not reduced at the site of fracture. These findings question whether measurements of bone mineral density may be used to assess risk of hip fracture. The mechanisms leading to the irregular relationship between bone density and strength are still uncertain within literature and investigated to greater extent in clinical applications. Finite element analysis within this study simulated physiological loading of the femoral neck. No significant changes in femoral neck strength were found across doses of proton or 28silicon head-only radiation. Future work includes performing mechanical testing of the bone samples. Moving from mouse to larger animal models may also provide the increased lifespan for assessing the long-term outcomes of radiation exposure.
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25
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Van den Wyngaert T, Tombal B. The changing role of radium-223 in metastatic castrate-resistant prostate cancer: has the EMA missed the mark with revising the label? THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING : OFFICIAL PUBLICATION OF THE ITALIAN ASSOCIATION OF NUCLEAR MEDICINE (AIMN) [AND] THE INTERNATIONAL ASSOCIATION OF RADIOPHARMACOLOGY (IAR), [AND] SECTION OF THE SOCIETY OF RADIOPHARMACEUTICAL CHEMISTRY AND BIOLOGY 2019; 63:170-182. [PMID: 31298017 DOI: 10.23736/s1824-4785.19.03205-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Radium-223 (223Ra) is a life-prolonging treatment in symptomatic men with metastatic castrate-resistant prostate cancer (mCRPC) and bone metastases, but no visceral disease, regardless of prior treatment with docetaxel. Together with four other drugs (i.e. abiraterone, cabazitaxel, docetaxel, enzalutamide), it has been available for clinical use since 2013 and has been shown to also provide benefits in quality-of-life and societal benefits. However, in 2018 the European Medicines Agency ruled to restrict the use of radium-223 to a more advanced disease setting after at least two lines of one or the other life-prolonging agent. This decision was triggered by the results of a safety interim analysis of ERA-223, a trial investigating the combination of 223Ra and abiraterone versus abiraterone alone in patients without prior chemotherapy (with the exception of adjuvant treatment) with asymptomatic bone predominant mCRPC. That safety analysis showed an early increased risk of fracture and deaths with the combination treatment. This review critically appraises the available and emerging data with 223Ra treatment in an attempt to assess the appropriateness of the revised label of radium-223.
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Affiliation(s)
- Tim Van den Wyngaert
- Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium - .,Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium -
| | - Bertrand Tombal
- Department of Urology, Saint Luc University Clinic, Brussels, Belgium.,Institute of Clinical Research, Catholic University of Louvain, Brussels, Belgium
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26
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Deyhle RT, Wong CP, Martin SA, McDougall MQ, Olson DA, Branscum AJ, Menn SA, Iwaniec UT, Hamby DM, Turner RT. Maintenance of Near Normal Bone Mass and Architecture in Lethally Irradiated Female Mice following Adoptive Transfer with as few as 750 Purified Hematopoietic Stem Cells. Radiat Res 2019; 191:413-427. [PMID: 30870097 DOI: 10.1667/rr15164.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Total-body irradiation (TBI) followed by transfer of bone marrow cells from donors is routinely performed in immunology research and can be used to manipulate differentiation and/or function of bone cells. However, exposure to high-dose radiation can result in irreversible osteopenia, and transfer of heterogeneous cell populations can complicate interpretation of results. The goal of this research was to establish an approach for reconstituting bone marrow using small numbers of purified donor-derived hematopoietic stem cells (HSCs) without negatively affecting bone metabolism. Gamma-irradiated (9 Gy) WBB6F1 mice were engrafted with bone marrow cells (5 × 106 cells) or purified HSCs (3,000 cells) obtained from GFP transgenic mice. In vivo analysis and in vitro differentiation assays performed two months later established that both methods were effective in reconstituting the hematopoietic compartment with donor-derived cells. We confirmed these findings by engrafting C57Bl/6 (B6) mice with bone marrow cells or purified HSCs from CD45.1 B6 congenic mice. We next performed adoptive transfer of purified HSCs (750 cells) into WBB6F1 and radiosensitive KitW/W-v mice and evaluated the skeleton two months later. Minimal differences were observed between controls and WBB6F1-engrafted mice that received fractionated doses of 2 × 5 Gy. Kitw/wv mice lost weight and became osteopenic after 2 × 5 Gy irradiations but these abnormalities were negligible after 5 Gy irradiation. Importantly, adoptive transfer of wild-type cells into Kitw/wv mice restored normal Kit expression in bone marrow. Together, these findings provide strong evidence for efficient engraftment with purified HSCs after lethal TBI with minimal collateral damage to bone. This approach will be useful for investigating mechanisms by which hematopoietic lineage cells regulate bone metabolism.
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Affiliation(s)
- Richard T Deyhle
- a Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331.,c Nuclear Science and Engineering, Oregon State University, Corvallis, Oregon 97331.,f Belgian Nuclear Research Centre (SCK•CEN), Boeretang 200, BE-2400 Mol, Belgium
| | - Carmen P Wong
- a Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331
| | - Stephen A Martin
- a Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331
| | - Melissa Q McDougall
- a Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331
| | - Dawn A Olson
- a Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331
| | - Adam J Branscum
- b Biostatistics Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331
| | - Scott A Menn
- d Radiation Center, Oregon State University, Corvallis, Oregon 97331
| | - Urszula T Iwaniec
- a Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331.,e Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon 97331
| | - David M Hamby
- c Nuclear Science and Engineering, Oregon State University, Corvallis, Oregon 97331
| | - Russell T Turner
- a Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon 97331.,e Center for Healthy Aging Research, Oregon State University, Corvallis, Oregon 97331
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27
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Mustafy T, Benoit A, Londono I, Moldovan F, Villemure I. Can repeated in vivo micro-CT irradiation during adolescence alter bone microstructure, histomorphometry and longitudinal growth in a rodent model? PLoS One 2018; 13:e0207323. [PMID: 30439999 PMCID: PMC6237372 DOI: 10.1371/journal.pone.0207323] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 10/29/2018] [Indexed: 11/18/2022] Open
Abstract
In vivo micro-computed tomography (micro-CT) can monitor longitudinal changes in bone mass and microstructure in small rodents but imposing high doses of radiation can damage the bone tissue. However, the effect of weekly micro-CT scanning during the adolescence on bone growth and architecture is still unknown. The right proximal tibia of male Sprague-Dawley rats randomized into three dose groups of 0.83, 1.65 and 2.47 Gy (n = 11/group) were CT scanned at weekly intervals from 4th to 12th week of age. The left tibia was used as a control and scanned only at the last time point. Bone marrow cells were investigated, bone growth rates and histomorphometric analyses were performed, and bone structural parameters were determined for both left and right tibiae. Radiation doses of 1.65 and 2.47 Gy affected bone marrow cells, heights of the proliferative and hypertrophic zones, and bone growth rates in the irradiated tibiae. For the 1.65 Gy group, irradiated tibiae resulted in lower BMD, Tb.Th, Tb.N and a higher Tb.Sp compared with the control tibiae. A decrease in BMD, BV/TV, Tb.Th, Tb.N and an increase in Tb.Sp were observed between the irradiated and control tibiae for the 2.47 Gy group. For cortical bone parameters, no effects were noticed for 1.65 and 0.83 Gy groups, but a lower Ct.Th was observed for 2.47 Gy group. Tibial bone development was adversely impacted and trabecular bone, together with bone marrow cells, were negatively affected by the 1.65 and 2.47 Gy radiation doses. Cortical bone microstructure was affected for 2.47 Gy group. However, bone development and morphometry were not affected for 0.83 Gy group. These findings can be used as a proof of concept for using the reasonable high-quality image acquisition under 0.83 Gy radiation doses during the adolescent period of rats without interfering with the bone development process.
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Affiliation(s)
- Tanvir Mustafy
- Department of Mechanical Engineering, École Polytechnique of Montréal, Station Centre-Ville, Montréal, Québec, Canada
- Sainte-Justine University Hospital Center, Montréal, Québec, Canada
| | - Aurélie Benoit
- Department of Mechanical Engineering, École Polytechnique of Montréal, Station Centre-Ville, Montréal, Québec, Canada
- Sainte-Justine University Hospital Center, Montréal, Québec, Canada
| | - Irène Londono
- Sainte-Justine University Hospital Center, Montréal, Québec, Canada
| | - Florina Moldovan
- Sainte-Justine University Hospital Center, Montréal, Québec, Canada
- Department of Stomatology, Faculty of Dentistry, Université de Montréal, Montreal, Station Centre-Ville, Montréal, Québec, Canada
| | - Isabelle Villemure
- Department of Mechanical Engineering, École Polytechnique of Montréal, Station Centre-Ville, Montréal, Québec, Canada
- Sainte-Justine University Hospital Center, Montréal, Québec, Canada
- * E-mail:
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28
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Cho IC, Chen FH, Chao TC, Tung CJ. A Monte Carlo study of bone-tissue interface microdosimeters. Appl Radiat Isot 2018; 140:193-200. [PMID: 30048920 DOI: 10.1016/j.apradiso.2018.07.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/28/2018] [Accepted: 07/13/2018] [Indexed: 11/26/2022]
Abstract
Radiation-induced bone diseases were frequently reported in radiotherapy patients. To study the diseases, microdosimeters were constructed with walls of A150-A150, A150-B100, B100-A150 and B100-B100 interfaces. Monte Carlo simulations of these microdosimeters were performed to determine the lineal energy spectra of an interface site at different depths in water for 230 MeV protons. Comparing these spectra with data of ICRU tissue and bone walls, better agreements were found at shallow depths for protons and delta-rays than deep depths for nuclear interactions.
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Affiliation(s)
- I-Chun Cho
- Department of Medical Imaging and Radiological Sciences, Chang Gung University, Guishan Dist., Taoyuan City 333, Taiwan; Medical Physics Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, Guishan Dist., Taoyuan City 333, Taiwan
| | - Fang-Hsin Chen
- Department of Medical Imaging and Radiological Sciences, Chang Gung University, Guishan Dist., Taoyuan City 333, Taiwan; Medical Physics Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, Guishan Dist., Taoyuan City 333, Taiwan
| | - Tsi-Chian Chao
- Department of Medical Imaging and Radiological Sciences, Chang Gung University, Guishan Dist., Taoyuan City 333, Taiwan; Medical Physics Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, Guishan Dist., Taoyuan City 333, Taiwan
| | - Chuan-Jong Tung
- Department of Medical Imaging and Radiological Sciences, Chang Gung University, Guishan Dist., Taoyuan City 333, Taiwan; Medical Physics Research Center, Institute for Radiological Research, Chang Gung University and Chang Gung Memorial Hospital, Guishan Dist., Taoyuan City 333, Taiwan.
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29
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Meganck JA, Liu B. Dosimetry in Micro-computed Tomography: a Review of the Measurement Methods, Impacts, and Characterization of the Quantum GX Imaging System. Mol Imaging Biol 2018; 19:499-511. [PMID: 27957647 PMCID: PMC5498628 DOI: 10.1007/s11307-016-1026-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Purpose X-ray micro-computed tomography (μCT) is a widely used imaging modality in preclinical research with applications in many areas including orthopedics, pulmonology, oncology, cardiology, and infectious disease. X-rays are a form of ionizing radiation and, therefore, can potentially induce damage and cause detrimental effects. Previous reviews have touched on these effects but have not comprehensively covered the possible implications on study results. Furthermore, interpreting data across these studies is difficult because there is no widely accepted dose characterization methodology for preclinical μCT. The purpose of this paper is to ensure in vivo μCT studies can be properly designed and the data can be appropriately interpreted. Procedures Studies from the scientific literature that investigate the biological effects of radiation doses relevant to μCT were reviewed. The different dose measurement methodologies used in the peer-reviewed literature were also reviewed. The CT dose index 100 (CTDI100) was then measured on the Quantum GX μCT instrument. A low contrast phantom, a hydroxyapatite phantom, and a mouse were also imaged to provide examples of how the dose can affect image quality. Results Data in the scientific literature indicate that scenarios exist where radiation doses used in μCT imaging are high enough to potentially bias experimental results. The significance of this effect may relate to the study outcome and tissue being imaged. CTDI100 is a reasonable metric to use for dose characterization in μCT. Dose rates in the Quantum GX vary based on the amount of material in the beam path and are a function of X-ray tube voltage. The CTDI100 in air for a Quantum GX can be as low as 5.1 mGy for a 50 kVp scan and 9.9 mGy for a 90 kVp scan. This dose is low enough to visualize bone both in a mouse image and in a hydroxyapatite phantom, but applications requiring higher resolution in a mouse or less noise in a low-contrast phantom benefit from longer scan times with increased dose. Conclusions Dose management should be considered when designing μCT studies. Dose rates in the Quantum GX are compatible with longitudinal μCT imaging.
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Affiliation(s)
- Jeffrey A Meganck
- Research and Development, Life Sciences Technology, PerkinElmer, 68 Elm Street, Hopkinton, MA, 01748, USA.
| | - Bob Liu
- Department of Radiology, Massachusetts General Hospital, Boston, MA, USA
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30
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Sayed AA, Abbas OA, Saad MA, Marie MAS. Cicer arietinum extract ameliorate γ-irradiation disorders via modulation of oxidative/antioxidative pathway. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2018; 183:46-56. [PMID: 29684720 DOI: 10.1016/j.jphotobiol.2018.04.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/08/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Ionized radiations trigger thoughtful adverse hazards through multiple organ dysfunctions. Recently, antioxidant-based biodrugs are used to prevent and treat ionizing radiation hazards. The present study aimed to investigate the prospective ameliorative effect of Cicer arietinum extract (CAE) against γ-irradiation and the pathway of this amelioration in male albino rats. Twenty four rats were allocated into four groups; (i) control group, (ii) CAE group in which rats treated with a dosage of 500 mg CAE/kg b.wt, (iii) γ-irradiated group in which rats exposed to 6Gy γ-irradiation, (iv) γ-irradiated+CAE group; rats of this group treated with CAE 1 h post exposure. All rats treated for 21 days. Liver, kidney and femoral bone were rapidly excised and homogenized for the biochemical analysis. Energy dispersive X-ray (EDX) and inductively coupled plasma emission spectrometer (ICP) analyses exhibit that γ-irradiation elicits significant change in the essential trace elements content in liver, kidney, and bone. Further, significant increases in TBARS and H2O2 contents accompanied by significant decreases in GSH, SOD, CAT, and GPx activities in liver, kidney and bone tissues were recorded in the γ-irradiated rats compared to control group. Additionally, marked reduction in the thickness of cortical bone was recorded in rats exposed to γ-irradiation. Conversely, CAE (500 mg/kg b.wt, p.o) administration for 21 days to γ-irradiated rats effectively reverses most of the altered parameters of the γ-irradiated rats. In conclusion, the present findings suggested that CAE is a potential agent that can be used against radiation hazards. This effect may be owing to its antioxidant mechanism, as CAE has an inhibitory effect against hydrogen peroxide (H2O2) and superoxide radical (O2·-) beside its ferric reducing antioxidant power (FRAP). This finding recommended that CAE can be utilized clinically to mitigate ionized radiation-induced hazard effects.
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Affiliation(s)
- Amany A Sayed
- Zoology Department, Faculty of Science, Cairo University, Giza, Egypt.
| | - Osama A Abbas
- Radiation Research Department, Atomic Energy Authority, Cairo, Egypt
| | - Mona A Saad
- Middle Eastern Regional Radioisotopes Center for Arab Countries, Egypt
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Lakhwani OP, Jindal M, Kaur O, Chandoke RK, Kapoor SK. Effect of bone bank processing on bone mineral density, histomorphometry & biomechanical strength of retrieved femoral head. Indian J Med Res 2018; 146:S45-S50. [PMID: 29578194 PMCID: PMC5890595 DOI: 10.4103/ijmr.ijmr_739_15] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Background & objectives: Standard processing of the bone grafts involves deep-freezing and sterilization with gamma irradiation which may alter mechanical properties of the bone graft. This study was aimed at measuring the effect of bone bank processing on the mechanical properties of bone allograft and its correlation with bone mineral density [BMD, dual-energy X-ray absorptiometry (DEXA Scan)] and histomorphometric indices. Methods: Femoral heads retrieved from patients undergoing hip replacement surgeries were used as the material. Twenty femoral heads were under taken in the study. Each femoral head was cut into two equal cubes. One cube was subjected to BMD measurement using DEXA Scan followed by unilateral compression test. Histomorphometric indices such as trabecular number (Tb. N.), trabecular separation (Tb. S.), trabecular thickness (Tb. T.) and bone volume (B.V.) were calculated on the same specimen by a computer software. The other cube was kept in deep freezer (−76°C) for a minimum of three weeks, followed by gamma irradiation and subjected to similar tests. Results: Results were compared in pre- and post-processed bone specimens. A significant loss of biomechanical strength (P<0.001) with mean a loss of 18.90 per cent was found in post-processed samples in uniaxial compression tests. Similarly, BMD (mean decrease by 13.8%, P<0.01) and histomorphometric indices such as Tb. T. (mean decrease by 12.37%, P<0.01), Tb. S. (mean increase by 12.60%, P<0.001) and B.V. (mean decrease by 20.84%, P<0.01) were found. However, Tb. N. was not significantly affected. Interpretation & conclusions: The current method of processing of bone allografts i.e. deep-freezing and gamma irradiation appeared to cause a significant reduction in the biomechanical strength of allogenic bone which was more suitable to be use in the morselized form. Appropriate consideration for decreased strength needs to be given when using allogenic bone graft as a structural graft.
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Affiliation(s)
- O P Lakhwani
- Department of Orthopaedics, Employees' State Insurance Corporation - Post Graduate Institute of Medical Sciences and Research, New Delhi, India
| | - M Jindal
- Department of Orthopaedics, Employees' State Insurance Corporation - Post Graduate Institute of Medical Sciences and Research, New Delhi, India
| | - Omkar Kaur
- Department of Pathology, Employees' State Insurance Corporation - Post Graduate Institute of Medical Sciences and Research, New Delhi, India
| | - R K Chandoke
- Department of Pathology, Employees' State Insurance Corporation - Post Graduate Institute of Medical Sciences and Research, New Delhi, India
| | - S K Kapoor
- Department of Orthopaedics, Employees' State Insurance Corporation - Post Graduate Institute of Medical Sciences and Research, New Delhi, India
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32
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Wang Y, Chang J, Li X, Pathak R, Sridharan V, Jones T, Mao XW, Nelson G, Boerma M, Hauer-Jensen M, Zhou D, Shao L. Low doses of oxygen ion irradiation cause long-term damage to bone marrow hematopoietic progenitor and stem cells in mice. PLoS One 2017; 12:e0189466. [PMID: 29232383 PMCID: PMC5726652 DOI: 10.1371/journal.pone.0189466] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 11/28/2017] [Indexed: 11/19/2022] Open
Abstract
During deep space missions, astronauts will be exposed to low doses of charged particle irradiation. The long-term health effects of these exposures are largely unknown. We previously showed that low doses of oxygen ion (16O) irradiation induced acute damage to the hematopoietic system, including hematopoietic progenitor and stem cells in a mouse model. However, the chronic effects of low dose 16O irradiation remain undefined. In the current study, we investigated the long-term effects of low dose 16O irradiation on the mouse hematopoietic system. Male C57BL/6J mice were exposed to 0.05 Gy, 0.1 Gy, 0.25 Gy and 1.0 Gy whole body 16O (600 MeV/n) irradiation. The effects of 16O irradiation on bone marrow (BM) hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) were examined three months after the exposure. The results showed that the frequencies and numbers of BM HPCs and HSCs were significantly reduced in 0.1 Gy, 0.25 Gy and 1.0 Gy irradiated mice compared to 0.05 Gy irradiated and non-irradiated mice. Exposure of mice to low dose 16O irradiation also significantly reduced the clongenic function of BM HPCs determined by the colony-forming unit assay. The functional defect of irradiated HSCs was detected by cobblestone area-forming cell assay after exposure of mice to 0.1 Gy, 0.25 Gy and 1.0 Gy of 16O irradiation, while it was not seen at three months after 0.5 Gy and 1.0 Gy of γ-ray irradiation. These adverse effects of 16O irradiation on HSCs coincided with an increased intracellular production of reactive oxygen species (ROS). However, there were comparable levels of cellular apoptosis and DNA damage between irradiated and non-irradiated HPCs and HSCs. These data suggest that exposure to low doses of 16O irradiation induces long-term hematopoietic injury, primarily via increased ROS production in HSCs.
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Affiliation(s)
- Yingying Wang
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Jianhui Chang
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Xin Li
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Rupak Pathak
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Vijayalakshmi Sridharan
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Tamako Jones
- Department of Basic Sciences, Division of Radiation Research, School of Medicine, Loma Linda University, Loma Linda, CA, United States of America
| | - Xiao Wen Mao
- Department of Basic Sciences, Division of Radiation Research, School of Medicine, Loma Linda University, Loma Linda, CA, United States of America
| | - Gregory Nelson
- Department of Basic Sciences, Division of Radiation Research, School of Medicine, Loma Linda University, Loma Linda, CA, United States of America
| | - Marjan Boerma
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Martin Hauer-Jensen
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Daohong Zhou
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
| | - Lijian Shao
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America
- * E-mail:
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33
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Shanmugarajan S, Zhang Y, Moreno-Villanueva M, Clanton R, Rohde LH, Ramesh GT, Sibonga JD, Wu H. Combined Effects of Simulated Microgravity and Radiation Exposure on Osteoclast Cell Fusion. Int J Mol Sci 2017; 18:ijms18112443. [PMID: 29156538 PMCID: PMC5713410 DOI: 10.3390/ijms18112443] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Revised: 11/12/2017] [Accepted: 11/15/2017] [Indexed: 12/11/2022] Open
Abstract
The loss of bone mass and alteration in bone physiology during space flight are one of the major health risks for astronauts. Although the lack of weight bearing in microgravity is considered a risk factor for bone loss and possible osteoporosis, organisms living in space are also exposed to cosmic radiation and other environmental stress factors. As such, it is still unclear as to whether and by how much radiation exposure contributes to bone loss during space travel, and whether the effects of microgravity and radiation exposure are additive or synergistic. Bone is continuously renewed through the resorption of old bone by osteoclast cells and the formation of new bone by osteoblast cells. In this study, we investigated the combined effects of microgravity and radiation by evaluating the maturation of a hematopoietic cell line to mature osteoclasts. RAW 264.7 monocyte/macrophage cells were cultured in rotating wall vessels that simulate microgravity on the ground. Cells under static 1g or simulated microgravity were exposed to γ rays of varying doses, and then cultured in receptor activator of nuclear factor-κB ligand (RANKL) for the formation of osteoclast giant multinucleated cells (GMCs) and for gene expression analysis. Results of the study showed that radiation alone at doses as low as 0.1 Gy may stimulate osteoclast cell fusion as assessed by GMCs and the expression of signature genes such as tartrate resistant acid phosphatase (Trap) and dendritic cell-specific transmembrane protein (Dcstamp). However, osteoclast cell fusion decreased for doses greater than 0.5 Gy. In comparison to radiation exposure, simulated microgravity induced higher levels of cell fusion, and the effects of these two environmental factors appeared additive. Interestingly, the microgravity effect on osteoclast stimulatory transmembrane protein (Ocstamp) and Dcstamp expressions was significantly higher than the radiation effect, suggesting that radiation may not increase the synthesis of adhesion molecules as much as microgravity.
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Affiliation(s)
- Srinivasan Shanmugarajan
- NASA Johnson Space Center, Houston, TX 77058, USA.
- Department of Biological and Environmental Sciences, University of Houston Clear Lake, Houston, TX 77058, USA.
| | - Ye Zhang
- NASA Kennedy Space Center, Cape Canaveral, FL 32899, USA.
| | - Maria Moreno-Villanueva
- NASA Johnson Space Center, Houston, TX 77058, USA.
- Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
| | - Ryan Clanton
- Department of Nuclear Engineering, Texas A & M University, College Station, TX 77843, USA.
| | - Larry H Rohde
- Department of Biological and Environmental Sciences, University of Houston Clear Lake, Houston, TX 77058, USA.
| | | | | | - Honglu Wu
- NASA Johnson Space Center, Houston, TX 77058, USA.
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34
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Xie Y, Yan JF, Ma JY, Li HY, Ye YC, Zhang YS, Zhang H. Evaluation of the toxicity of iron-ion irradiation in murine bone marrow dendritic cells via increasing the expression of indoleamine 2,3-dioxygenase 1. Toxicol Res (Camb) 2017; 6:958-968. [PMID: 30090556 PMCID: PMC6061850 DOI: 10.1039/c7tx00194k] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/24/2017] [Indexed: 12/13/2022] Open
Abstract
High linear energy transfer radiation is known to deposit higher energy in tissues and cause greater toxicity compared to low-LET irradiation. Local immunosuppression is frequently observed after irradiation (IR). Dendritic cells (DCs) play important roles in the initiation and maintenance of the immune response. The dysfunction of DCs contributes to tumor evasion and growth. However, molecular mechanisms underlying the establishment of immune tolerance induced by heavy ion IR through this DC population are poorly understood. Therefore, here we report our findings on the dysfunction of bone marrow-derived dendritic cells (BMDCs) induced by 1 Gy iron ion radiation and promotions of expressions of JNK1/2/3, indoleamine 2,3-dioxygenase 1 (IDO1), p-ERK1/2 and p38/MAPK; and decrease of IDO2, MHC class II, CD40, CD80 expressions and IFN-γ and TNF-α secretion after total-body IR in mice. JNK+IDO1+ BMDCs showed up-expression of p-ERK1/2 and p-p38/MAPK, reduced expression of MHC class II and CD80, and were not able to effectively stimulate allogeneic spleen T cells. The inhibition of IDO1 expressions could partly restore the function of BMDCs. In all, our study shows that elevated JNK and IDO1 expression induced by Fe ion IR could result in dysfunction of BMDCs via p-p38/MAPK and p-ERK1/2 signal pathway, and it may represent a new mechanism in radiation-induced immune tolerance.
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Affiliation(s)
- Yi Xie
- Institute of Modern Physics , Chinese Academy of Sciences , 509 Nanchang Road , Lanzhou 730000 , China . ; ; Tel: +86 931 4969344
- CAS Key Laboratory of Heavy Ion Radiation Biology and Medicine , Institute of Modern Physics , Lanzhou 730000 , Gansu , China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine , Gansu Province , Lanzhou 730000 , China
| | - Jun-Fang Yan
- Institute of Modern Physics , Chinese Academy of Sciences , 509 Nanchang Road , Lanzhou 730000 , China . ; ; Tel: +86 931 4969344
- CAS Key Laboratory of Heavy Ion Radiation Biology and Medicine , Institute of Modern Physics , Lanzhou 730000 , Gansu , China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine , Gansu Province , Lanzhou 730000 , China
- Graduate School of University of Chinese Academy of Sciences , Beijing 100039 , China
| | - Jing-Yi Ma
- School of Pharmaceutical Sciences , Sun Yat-sen University , Guangzhou 510006 , China
| | - Hong-Yan Li
- Institute of Modern Physics , Chinese Academy of Sciences , 509 Nanchang Road , Lanzhou 730000 , China . ; ; Tel: +86 931 4969344
- CAS Key Laboratory of Heavy Ion Radiation Biology and Medicine , Institute of Modern Physics , Lanzhou 730000 , Gansu , China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine , Gansu Province , Lanzhou 730000 , China
| | - Yan-Cheng Ye
- Gansu Wuwei Tumor Hospital , Wuwei , 733000 , China
| | | | - Hong Zhang
- Institute of Modern Physics , Chinese Academy of Sciences , 509 Nanchang Road , Lanzhou 730000 , China . ; ; Tel: +86 931 4969344
- CAS Key Laboratory of Heavy Ion Radiation Biology and Medicine , Institute of Modern Physics , Lanzhou 730000 , Gansu , China
- Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine , Gansu Province , Lanzhou 730000 , China
- Gansu Wuwei Tumor Hospital , Wuwei , 733000 , China
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35
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Yu K, Doherty AH, Genik PC, Gookin SE, Roteliuk DM, Wojda SJ, Jiang ZS, McGee-Lawrence ME, Weil MM, Donahue SW. Mimicking the effects of spaceflight on bone: Combined effects of disuse and chronic low-dose rate radiation exposure on bone mass in mice. LIFE SCIENCES IN SPACE RESEARCH 2017; 15:62-68. [PMID: 29198315 DOI: 10.1016/j.lssr.2017.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/31/2017] [Accepted: 08/11/2017] [Indexed: 06/07/2023]
Abstract
During spaceflight, crewmembers are subjected to biomechanical and biological challenges including microgravity and radiation. In the skeleton, spaceflight leads to bone loss, increasing the risk of fracture. Studies utilizing hindlimb suspension (HLS) as a ground-based model of spaceflight often neglect the concomitant effects of radiation exposure, and even when radiation is accounted for, it is often delivered at a high-dose rate over a very short period of time, which does not faithfully mimic spaceflight conditions. This study was designed to investigate the skeletal effects of low-dose rate gamma irradiation (8.5 cGy gamma radiation per day for 20 days, amounting to a total dose of 1.7 Gy) when administered simultaneously to disuse from HLS. The goal was to determine whether continuous, low-dose rate radiation administered during disuse would exacerbate bone loss in a murine HLS model. Four groups of 16 week old female C57BL/6 mice were studied: weight bearing + no radiation (WB+NR), HLS + NR, WB + radiation exposure (WB+RAD), and HLS+RAD. Surprisingly, although HLS led to cortical and trabecular bone loss, concurrent radiation exposure did not exacerbate these effects. Our results raise the possibility that mechanical unloading has larger effects on the bone loss that occurs during spaceflight than low-dose rate radiation.
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Affiliation(s)
- Kanglun Yu
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China; Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Alison H Doherty
- Department of Medical Education, WWAMI Medical Education Program, University of Wyoming, Laramie, WY, USA
| | - Paula C Genik
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Sara E Gookin
- Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA
| | - Danielle M Roteliuk
- Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA
| | - Samantha J Wojda
- Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA
| | - Zhi-Sheng Jiang
- Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan, China
| | - Meghan E McGee-Lawrence
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, USA; Department of Orthopaedic Surgery, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Michael M Weil
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, USA
| | - Seth W Donahue
- Department of Mechanical Engineering, Colorado State University, Fort Collins, CO, USA.
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36
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Tong L, Zhu G, Wang J, Sun R, He F, Zhai J. Suppressing angiogenesis regulates the irradiation-induced stimulation on osteoclastogenesis in vitro. J Cell Physiol 2017; 233:3429-3438. [PMID: 28941279 DOI: 10.1002/jcp.26196] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 09/15/2017] [Indexed: 01/08/2023]
Abstract
Ionizing radiation-induced bone loss is a potential health concern in radiotherapy, occupational exposure, and astronauts. Although impaired bone vasculature and reduced proliferation of bone-forming osteoblasts has been implicated in this process, it has not been clearly characterized that whether radiation affects the growth of bone-resorbing osteoclasts. The molecular crosstalk between different cell populations in the skeletal system has not yet been elucidated in detail, especially between the increased bone resorption at early stage of post-irradiation and bone marrow-derived endothelial progenitor cells (BM-EPCs). In order to further understand the mechanisms involved in radiation-induced bone loss at the cellular level, we assessed the effects of irradiation on angiogenesis of BM-EPCs and osteoclastogenesis of receptor activator for nuclear factor-κB ligand (RANKL)-stimulated RAW 264.7 cells and crosstalk between these cell populations. We herein found significantly dysfunction of BM-EPCs in response to irradiation at a dose of 2 Gy, including inhibited proliferation, migration, tube-forming abilities, and downregulated expression of pro-angiogenesis vascular endothelial growth factors A (VEGF A). Meanwhile, we observed that irradiation promoted osteoclastogenesis of RANKL-stimulated RAW 264.7 cells directly or indirectly. These results provide quantitative evidences of irradiation induced osteoclastogenesis at a cellular level, and strongly suggest the involvement of osteoclastogenesis, angiogenesis and crosstalk between bone marrow cells in the radiation-induced bone loss. This study may provide new insights for the early diagnosis and intervention of bone loss post-irradiation.
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Affiliation(s)
- Ling Tong
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Guoying Zhu
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Jianping Wang
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Ruilian Sun
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Feilong He
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Jianglong Zhai
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
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Alwood JS, Tran LH, Schreurs AS, Shirazi-Fard Y, Kumar A, Hilton D, Tahimic CGT, Globus RK. Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System. Int J Mol Sci 2017; 18:ijms18102117. [PMID: 28994728 PMCID: PMC5666799 DOI: 10.3390/ijms18102117] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 09/29/2017] [Accepted: 09/30/2017] [Indexed: 12/12/2022] Open
Abstract
Space radiation may pose a risk to skeletal health during subsequent aging. Irradiation acutely stimulates bone remodeling in mice, although the long-term influence of space radiation on bone-forming potential (osteoblastogenesis) and possible adaptive mechanisms are not well understood. We hypothesized that ionizing radiation impairs osteoblastogenesis in an ion-type specific manner, with low doses capable of modulating expression of redox-related genes. 16-weeks old, male, C57BL6/J mice were exposed to low linear-energy-transfer (LET) protons (150 MeV/n) or high-LET 56Fe ions (600 MeV/n) using either low (5 or 10 cGy) or high (50 or 200 cGy) doses at NASA's Space Radiation Lab. Five weeks or one year after irradiation, tissues were harvested and analyzed by microcomputed tomography for cancellous microarchitecture and cortical geometry. Marrow-derived, adherent cells were grown under osteoblastogenic culture conditions. Cell lysates were analyzed by RT-PCR during the proliferative or mineralizing phase of growth, and differentiation was analyzed by imaging mineralized nodules. As expected, a high dose (200 cGy), but not lower doses, of either 56Fe or protons caused a loss of cancellous bone volume/total volume. Marrow cells produced mineralized nodules ex vivo regardless of radiation type or dose; 56Fe (200 cGy) inhibited osteoblastogenesis by more than 90% (5 weeks and 1 year post-IR). After 5 weeks, irradiation (protons or 56Fe) caused few changes in gene expression levels during osteoblastogenesis, although a high dose 56Fe (200 cGy) increased Catalase and Gadd45. The addition of exogenous superoxide dismutase (SOD) protected marrow-derived osteoprogenitors from the damaging effects of exposure to low-LET (137Cs γ) when irradiated in vitro, but had limited protective effects on high-LET 56Fe-exposed cells. In sum, either protons or 56Fe at a relatively high dose (200 cGy) caused persistent bone loss, whereas only high-LET 56Fe increased redox-related gene expression, albeit to a limited extent, and inhibited osteoblastogenesis. Doses below 50 cGy did not elicit widespread responses in any parameter measured. We conclude that high-LET irradiation at 200 cGy impaired osteoblastogenesis and regulated steady-state gene expression of select redox-related genes during osteoblastogenesis, which may contribute to persistent bone loss.
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Affiliation(s)
- Joshua S Alwood
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Luan H Tran
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Ann-Sofie Schreurs
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Yasaman Shirazi-Fard
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Akhilesh Kumar
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Diane Hilton
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Candice G T Tahimic
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
- Wyle Laboratories, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Ruth K Globus
- Bone and Signaling Laboratory, Space BioSciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
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38
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Lima F, Swift JM, Greene ES, Allen MR, Cunningham DA, Braby LA, Bloomfield SA. Exposure to Low-Dose X-Ray Radiation Alters Bone Progenitor Cells and Bone Microarchitecture. Radiat Res 2017; 188:433-442. [PMID: 28771086 DOI: 10.1667/rr14414.1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Exposure to high-dose ionizing radiation during medical treatment exerts well-documented deleterious effects on bone health, reducing bone density and contributing to bone growth retardation in young patients and spontaneous fracture in postmenopausal women. However, the majority of human radiation exposures occur in a much lower dose range than that used in the radiation oncology clinic. Furthermore, very few studies have examined the effects of low-dose ionizing radiation on bone integrity and results have been inconsistent. In this study, mice were irradiated with a total-body dose of 0.17, 0.5 or 1 Gy to quantify the early (day 3 postirradiation) and delayed (day 21 postirradiation) effects of radiation on bone microarchitecture and bone marrow stromal cells (BMSCs). Female BALBc mice (4 months old) were divided into four groups: irradiated (0.17, 0.5 and 1 Gy) and sham-irradiated controls (0 Gy). Micro-computed tomography analysis of distal femur trabecular bone from animals at day 21 after exposure to 1 Gy of X-ray radiation revealed a 21% smaller bone volume (BV/TV), 22% decrease in trabecular numbers (Tb.N) and 9% greater trabecular separation (Tb.Sp) compared to sham-irradiated controls (P < 0.05). We evaluated the differentiation capacity of bone marrow stromal cells harvested at days 3 and 21 postirradiation into osteoblast and adipocyte cells. Osteoblast and adipocyte differentiation was decreased when cells were harvested at day 3 postirradiation but enhanced in cells isolated at day 21 postirradiation, suggesting a compensatory recovery process. Osteoclast differentiation was increased in 1 Gy irradiated BMSCs harvested at day 3 postirradiation, but not in those harvested at day 21 postirradiation, compared to controls. This study provides evidence of an early, radiation-induced decrease in osteoblast activity and numbers, as well as a later recovery effect after exposure to 1 Gy of X-rays, whereas osteoclastogenesis was enhanced. A better understanding of the effects of radiation on osteoprogenitor cell populations could lead to more effective therapeutic interventions that protect bone integrity for individuals exposed to low-dose ionizing radiation.
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Affiliation(s)
- Florence Lima
- a Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky 40536
| | - Joshua M Swift
- b Department of Health and Kinesiology, Texas A&M University, College Station, Texas 77843
| | - Elisabeth S Greene
- b Department of Health and Kinesiology, Texas A&M University, College Station, Texas 77843
| | - Matthew R Allen
- e Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - David A Cunningham
- b Department of Health and Kinesiology, Texas A&M University, College Station, Texas 77843
| | - Leslie A Braby
- c Department of Nuclear Engineering, Texas A&M University, College Station, Texas 77843
| | - Susan A Bloomfield
- b Department of Health and Kinesiology, Texas A&M University, College Station, Texas 77843.,d Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843
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39
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Sun R, Zhu G, Wang J, Tong L, Zhai J. Indirect effects of X-irradiation on proliferation and osteogenic potential of bone marrow mesenchymal stem cells in a local irradiated rat model. Mol Med Rep 2017; 15:3706-3714. [PMID: 28440500 PMCID: PMC5436268 DOI: 10.3892/mmr.2017.6464] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 04/03/2017] [Indexed: 02/06/2023] Open
Abstract
Cancer survivors after radiotherapy may suffer a variety of bone-related adverse side effects, including radioactive osteoporosis and fractures. Localized irradiation is a common treatment modality for malignancies. Recently, a series of reactions and injuries called indirect effects (remote changes in bone when other parts of the body are irradiated) have been reported on the indirect irradiated area of bone tissue after radiotherapy. To address this issue, we developed a rat localized irradiation model. Rats were irradiated with a single dose of X-rays to the left hind limbs, and bone marrow mesenchymal stem cells (BMMSCs) were isolated from bone marrow of the left (direct irradiated) and right (indirect irradiated) hind limbs 3, 7 and 14 days after irradiation, and assayed for the proliferation ability and osteogenic potential by alkaline phosphatase (ALP) activity, mineralization assay, RT-PCR and western blot analysis. The results showed that there were significant morphology changes in the BMMSCs from direct and indirect irradiated bone tissue with bigger cell bodies and increased granules. The proliferation of BMMSCs decreased both in the direct irradiated and non-irradiated bone tissue. The ALP expression and activities of BMMSCs from direct irradiated bone was consistently defected following a transient enhancement, the mRNA levels of RUNX2 and OCN, the protein expression of RUNX2, and the mineralization ability also showed the same trend. Simultaneously, in indirect irradiated group, the osteogenic potential indicators of BMMSCs decreased in the early stage of post-irradiation and were still impaired 14 days after irradiation. Our data demonstrate that localized irradiation may have both direct and indirect adverse effects on BMMSCs' proliferation and osteogenic potential into osteoblast, which may be the mechanism of radiation-induced abscopal impairment to the skeleton in the cancer radiotherapy-induced bone loss.
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Affiliation(s)
- Ruilian Sun
- Department of Radiation Protection, Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
| | - Guoying Zhu
- Department of Radiation Protection, Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
| | - Jianping Wang
- Department of Radiation Protection, Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
| | - Ling Tong
- Department of Radiation Protection, Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
| | - Jianglong Zhai
- Department of Radiation Protection, Institute of Radiation Medicine, Fudan University, Shanghai 200032, P.R. China
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40
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Chandra A, Lin T, Young T, Tong W, Ma X, Tseng WJ, Kramer I, Kneissel M, Levine MA, Zhang Y, Cengel K, Liu XS, Qin L. Suppression of Sclerostin Alleviates Radiation-Induced Bone Loss by Protecting Bone-Forming Cells and Their Progenitors Through Distinct Mechanisms. J Bone Miner Res 2017; 32:360-372. [PMID: 27635523 PMCID: PMC5476363 DOI: 10.1002/jbmr.2996] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 09/12/2016] [Accepted: 09/14/2016] [Indexed: 12/15/2022]
Abstract
Focal radiotherapy is frequently associated with skeletal damage within the radiation field. Our previous in vitro study showed that activation of Wnt/β-catenin pathway can overcome radiation-induced DNA damage and apoptosis of osteoblastic cells. Neutralization of circulating sclerostin with a monoclonal antibody (Scl-Ab) is an innovative approach for treating osteoporosis by enhancing Wnt/β-catenin signaling in bone. Together with the fact that focal radiation increases sclerostin amount in bone, we sought to determine whether weekly treatment with Scl-Ab would prevent focal radiotherapy-induced osteoporosis in mice. Micro-CT and histomorphometric analyses demonstrated that Scl-Ab blocked trabecular bone structural deterioration after radiation by partially preserving osteoblast number and activity. Consistently, trabecular bone in sclerostin null mice was resistant to radiation via the same mechanism. Scl-Ab accelerated DNA repair in osteoblasts after radiation by reducing the number of γ-H2AX foci, a DNA double-strand break marker, and increasing the amount of Ku70, a DNA repair protein, thus protecting osteoblasts from radiation-induced apoptosis. In osteocytes, apart from using similar DNA repair mechanism to rescue osteocyte apoptosis, Scl-Ab restored the osteocyte canaliculi structure that was otherwise damaged by radiation. Using a lineage tracing approach that labels all mesenchymal lineage cells in the endosteal bone marrow, we demonstrated that radiation damage to mesenchymal progenitors mainly involves shifting their fate to adipocytes and arresting their proliferation ability but not inducing apoptosis, which are different mechanisms from radiation damage to mature bone forming cells. Scl-Ab treatment partially blocked the lineage shift but had no effect on the loss of proliferation potential. Taken together, our studies provide proof-of-principle evidence for a novel use of Scl-Ab as a therapeutic treatment for radiation-induced osteoporosis and establish molecular and cellular mechanisms that support such treatment. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Abhishek Chandra
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Tiao Lin
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Musculoskeletal Oncology Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Tiffany Young
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei Tong
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoyuan Ma
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei-Ju Tseng
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ina Kramer
- Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Michaela Kneissel
- Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Michael A Levine
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Division of Endocrinology and Diabetes and the Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Yejia Zhang
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Philadelphia Veterans Affairs Medical Center and Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Keith Cengel
- Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - X Sherry Liu
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ling Qin
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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41
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Suman S, Kumar S, Fornace AJ, Datta K. Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine. Sci Rep 2016; 6:31853. [PMID: 27558773 PMCID: PMC4997262 DOI: 10.1038/srep31853] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 07/28/2016] [Indexed: 12/21/2022] Open
Abstract
Travel into outer space is fraught with risk of exposure to energetic heavy ion radiation such as 56Fe ions, which due to its high linear energy transfer (high-LET) characteristics deposits higher energy per unit volume of tissue traversed and thus more damaging to cells relative to low-LET radiation such as γ rays. However, estimates of human health risk from energetic heavy ion exposure are hampered due to lack of tissue specific in vivo molecular data. We investigated long-term effects of 56Fe radiation on adipokines and insulin-like growth factor 1 (IGF1) signaling axis in mouse intestine and colon. Six- to eight-week-old C57BL/6J mice were exposed to 1.6 Gy of 56Fe ions. Serum and tissues were collected up to twelve months post-irradiation. Serum was analyzed for leptin, adiponectin, IGF1, and IGF binding protein 3. Receptor expressions and downstream signaling pathway alterations were studied in tissues. Irradiation increased leptin and IGF1 levels in serum, and IGF1R and leptin receptor expression in tissues. When considered along with upregulated Jak2/Stat3 pathways and cell proliferation, our data supports the notion that space radiation exposure is a risk to endocrine alterations with implications for chronic pathophysiologic changes in gastrointestinal tract.
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Affiliation(s)
- Shubhankar Suman
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Santosh Kumar
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Albert J Fornace
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.,Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
| | - Kamal Datta
- Department of Biochemistry and Molecular &Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
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Macias BR, Lima F, Swift JM, Shirazi-Fard Y, Greene ES, Allen MR, Fluckey J, Hogan HA, Braby L, Wang S, Bloomfield SA. Simulating the Lunar Environment: Partial Weightbearing and High-LET Radiation-Induce Bone Loss and Increase Sclerostin-Positive Osteocytes. Radiat Res 2016; 186:254-63. [PMID: 27538114 DOI: 10.1667/rr13579.1] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Exploration missions to the Moon or Mars will expose astronauts to galactic cosmic radiation and low gravitational fields. Exposure to reduced weightbearing and radiation independently result in bone loss. However, no data exist regarding the skeletal consequences of combining low-dose, high-linear energy transfer (LET) radiation and partial weightbearing. We hypothesized that simulated galactic cosmic radiation would exacerbate bone loss in animals held at one-sixth body weight (G/6) without radiation exposure. Female BALB/cByJ four-month-old mice were randomly assigned to one of the following treatment groups: 1 gravity (1G) control; 1G with radiation; G/6 control; and G/6 with radiation. Mice were exposed to either silicon-28 or X-ray radiation. (28)Si radiation (300 MeV/nucleon) was administered at acute doses of 0 (sham), 0.17 and 0.5 Gy, or in three fractionated doses of 0.17 Gy each over seven days. X radiation (250 kV) was administered at acute doses of 0 (sham), 0.17, 0.5 and 1 Gy, or in three fractionated doses of 0.33 Gy each over 14 days. Bones were harvested 21 days after the first exposure. Acute 1 Gy X-ray irradiation during G/6, and acute or fractionated 0.5 Gy (28)Si irradiation during 1G resulted in significantly lower cancellous mass [percentage bone volume/total volume (%BV/TV), by microcomputed tomography]. In addition, G/6 significantly reduced %BV/TV compared to 1G controls. When acute X-ray irradiation was combined with G/6, distal femur %BV/TV was significantly lower compared to G/6 control. Fractionated X-ray irradiation during G/6 protected against radiation-induced losses in %BV/TV and trabecular number, while fractionated (28)Si irradiation during 1G exacerbated the effects compared to single-dose exposure. Impaired bone formation capacity, measured by percentage mineralizing surface, can partially explain the lower cortical bone thickness. Moreover, both partial weightbearing and (28)Si-ion exposure contribute to a higher proportion of sclerostin-positive osteocytes in cortical bone. Taken together, these data suggest that partial weightbearing and low-dose, high-LET radiation negatively impact maintenance of bone mass by lowering bone formation and increasing bone resorption. The impaired bone formation response is associated with sclerostin-induced suppression of Wnt signaling. Therefore, exposure to low-dose, high-LET radiation during long-duration spaceflight missions may reduce bone formation capacity, decrease cancellous bone mass and increase bone resorption. Future countermeasure strategies should aim to restore mechanical loads on bone to those experienced in one gravity. Moreover, low-doses of high-LET radiation during long-duration spaceflight should be limited or countermeasure strategies employed to mitigate bone loss.
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Affiliation(s)
| | | | | | | | | | - M R Allen
- g Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | | | - H A Hogan
- b Biomedical Engineering.,c Mechanical Engineering
| | | | - Suojin Wang
- f Statistics, Texas A&M University, College Station, Texas, 77843 and
| | - S A Bloomfield
- a Health and Kinesiology.,d Intercollegiate Faculty of Nutrition
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43
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Guo C, Li C, Yang K, Kang H, Xu X, Xu X, Deng L. Increased EZH2 and decreased osteoblastogenesis during local irradiation-induced bone loss in rats. Sci Rep 2016; 6:31318. [PMID: 27499068 PMCID: PMC4976370 DOI: 10.1038/srep31318] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 07/05/2016] [Indexed: 01/06/2023] Open
Abstract
Radiation therapy is commonly used to treat cancer patients but exhibits adverse effects, including insufficiency fractures and bone loss. Epigenetic regulation plays an important role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Here, we reported local bone changes after single-dose exposure to 137CS irradiation in rats. Femur bone mineral density (BMD) and trabecular bone volume in the tibia were significantly decreased at 12 weeks after irradiation. Micro-CT results showed that tBMD, Tb.h and Tb.N were also significantly reduced at 12 weeks after irradiation exposure. ALP-positive OB.S/BS was decreased by 42.3% at 2 weeks after irradiation and was decreased by 50.8% at 12 weeks after exposure. In contrast to the decreased expression of Runx2 and BMP2, we found EZH2 expression was significantly increased at 2 weeks after single-dose 137CS irradiation in BMSCs. Together, our results demonstrated that single-dose 137CS irradiation induces BMD loss and the deterioration of bone microarchitecture in the rat skeleton. Furthermore, EZH2 expression increased and osteoblastogenesis decreased after irradiation. The underlying mechanisms warrant further investigation.
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Affiliation(s)
- Changjun Guo
- Shanghai Key Laboratory for the Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. Address: No. 197, Rui Jin Er Road, Shanghai 200025 China
| | - Changwei Li
- Shanghai Key Laboratory for the Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. Address: No. 197, Rui Jin Er Road, Shanghai 200025 China
| | - Kai Yang
- Shanghai Key Laboratory for the Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. Address: No. 197, Rui Jin Er Road, Shanghai 200025 China
| | - Hui Kang
- Shanghai Key Laboratory for the Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. Address: No. 197, Rui Jin Er Road, Shanghai 200025 China
| | - Xiaoya Xu
- Department of Bone Metabolism, Institute of Radiation Medicine, Fudan University, Shanghai 200032, China. Address: No. 2094, Xietu Road, Shanghai 200032 China
| | - Xiangyang Xu
- Department of Orthopedics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. Address: No. 197, Rui Jin Er Road, Shanghai 200025 China
| | - Lianfu Deng
- Shanghai Key Laboratory for the Prevention and Treatment of Bone and Joint Diseases with Integrated Chinese-Western Medicine, Shanghai Institute of Traumatology and Orthopedics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine. Address: No. 197, Rui Jin Er Road, Shanghai 200025 China
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44
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Oest ME, Mann KA, Zimmerman ND, Damron TA. Parathyroid Hormone (1-34) Transiently Protects Against Radiation-Induced Bone Fragility. Calcif Tissue Int 2016; 98:619-30. [PMID: 26847434 PMCID: PMC4860360 DOI: 10.1007/s00223-016-0111-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 01/18/2016] [Indexed: 01/05/2023]
Abstract
Radiation therapy for soft tissue sarcoma or tumor metastases is frequently associated with damage to the underlying bone. Using a mouse model of limited field hindlimb irradiation, we assessed the ability of parathyroid hormone (1-34) fragment (PTH) delivery to prevent radiation-associated bone damage, including loss of mechanical strength, trabecular architecture, cortical bone volume, and mineral density. Female BALB/cJ mice received four consecutive doses of 5 Gy to a single hindlimb, accompanied by daily injections of either PTH or saline (vehicle) for 8 weeks, and were followed for 26 weeks. Treatment with PTH maintained the mechanical strength of irradiated femurs in axial compression for the first eight weeks of the study, and the apparent strength of irradiated femurs in PTH-treated mice was greater than that of naïve bones during this time. PTH similarly protected against radiation-accelerated resorption of trabecular bone and transient decrease in mid-diaphyseal cortical bone volume, although this benefit was maintained only for the duration of PTH delivery. Overall, PTH conferred protection against radiation-induced fragility and morphologic changes by increasing the quantity of bone, but only during the period of administration. Following cessation of PTH delivery, bone strength and trabecular volume fraction rapidly decreased. These data suggest that PTH does not negate the longer-term potential for osteoclastic bone resorption, and therefore, finite-duration treatment with PTH alone may not be sufficient to prevent late onset radiotherapy-induced bone fragility.
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Affiliation(s)
- Megan E Oest
- Department of Orthopedic Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA.
| | - Kenneth A Mann
- Department of Orthopedic Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA
| | - Nicholas D Zimmerman
- Department of Orthopedic Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA
| | - Timothy A Damron
- Department of Orthopedic Surgery, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA
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45
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Bloomfield SA, Martinez DA, Boudreaux RD, Mantri AV. Microgravity Stress: Bone and Connective Tissue. Compr Physiol 2016; 6:645-86. [PMID: 27065165 DOI: 10.1002/cphy.c130027] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The major alterations in bone and the dense connective tissues in humans and animals exposed to microgravity illustrate the dependency of these tissues' function on normal gravitational loading. Whether these alterations depend solely on the reduced mechanical loading of zero g or are compounded by fluid shifts, altered tissue blood flow, radiation exposure, and altered nutritional status is not yet well defined. Changes in the dense connective tissues and intervertebral disks are generally smaller in magnitude but occur more rapidly than those in mineralized bone with transitions to 0 g and during recovery once back to the loading provided by 1 g conditions. However, joint injuries are projected to occur much more often than the more catastrophic bone fracture during exploration class missions, so protecting the integrity of both tissues is important. This review focuses on the research performed over the last 20 years in humans and animals exposed to actual spaceflight, as well as on knowledge gained from pertinent ground-based models such as bed rest in humans and hindlimb unloading in rodents. Significant progress has been made in our understanding of the mechanisms for alterations in bone and connective tissues with exposure to microgravity, but intriguing questions remain to be solved, particularly with reference to biomedical risks associated with prolonged exploration missions.
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Affiliation(s)
- Susan A Bloomfield
- Department of Health & Kinesiology, Texas A&M University, College Station, Texas, USA
| | - Daniel A Martinez
- Department of Mechanical Engineering, University of Houston, Houston, Texas, USA
| | - Ramon D Boudreaux
- Biomedical Engineering, Texas A&M University, College Station, Texas, USA
| | - Anita V Mantri
- Department of Health & Kinesiology, Texas A&M University, College Station, Texas, USA.,Health Science Center School of Medicine, Texas A&M University, College Station, Texas, USA
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46
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Raber J, Allen AR, Weber S, Chakraborti A, Sharma S, Fike JR. Effect of behavioral testing on spine density of basal dendrites in the CA1 region of the hippocampus modulated by (56)Fe irradiation. Behav Brain Res 2016; 302:263-8. [PMID: 26801826 DOI: 10.1016/j.bbr.2016.01.035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Revised: 01/13/2016] [Accepted: 01/16/2016] [Indexed: 01/11/2023]
Abstract
A unique feature of the space radiation environment is the presence of high-energy charged particles, including (56)Fe ions, which can present a significant hazard to space flight crews during and following a mission. (56)Fe irradiation-induced cognitive changes often involve alterations in hippocampal function. These alterations might involve changes in spine morphology and density. In addition to irradiation, performing a cognitive task can also affect spine morphology. Therefore, it is often hard to determine whether changes in spine morphology and density are due to an environmental challenge or group differences in performance on cognitive tests. In this study, we tested the hypothesis that the ability of exploratory behavior to increase specific measures of hippocampal spine morphology and density is affected by (56)Fe irradiation. In sham-irradiated mice, exploratory behavior increased basal spine density in the CA1 region of the hippocampus and the enclosed blade of the dentate gyrus. These effects were not seen in irradiated mice. In addition, following exploratory behavior, there was a trend toward a decrease in the percent stubby spines on apical dendrites in the CA3 region of the hippocampus in (56)Fe-irradiated, but not sham-irradiated, mice. Other hippocampal regions and spine measures affected by (56)Fe irradiation showed comparable radiation effects in behaviorally naïve and cognitively tested mice. Thus, the ability of exploratory behavior to alter spine density and morphology in specific hippocampal regions is affected by (56)Fe irradiation.
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Affiliation(s)
- Jacob Raber
- Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, United States; Departments of Neurology, Radiation Medicine and Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, United States.
| | - Antiño R Allen
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States
| | - Sydney Weber
- Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, United States
| | - Ayanabha Chakraborti
- Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, CA 94110, United States; The Brain Research Institute at Monash Sunway, Selangor Darul Ehsan, Malaysia
| | - Sourabh Sharma
- Departments of Neurology, Radiation Medicine and Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, United States
| | - John R Fike
- Departments of Neurology, Radiation Medicine and Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, United States; Department of Radiation Oncology, University of California, San Francisco, CA 94110, United States
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47
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Datta K, Suman S, Kumar S, Fornace AJ. Colorectal Carcinogenesis, Radiation Quality, and the Ubiquitin-Proteasome Pathway. J Cancer 2016; 7:174-83. [PMID: 26819641 PMCID: PMC4716850 DOI: 10.7150/jca.13387] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 11/01/2015] [Indexed: 12/12/2022] Open
Abstract
Adult colorectal epithelium undergoes continuous renewal and maintains homeostatic balance through regulated cellular proliferation, differentiation, and migration. The canonical Wnt signaling pathway involving the transcriptional co-activator β-catenin is important for colorectal development and normal epithelial maintenance, and deregulated Wnt/β-catenin signaling has been implicated in colorectal carcinogenesis. Colorectal carcinogenesis has been linked to radiation exposure, and radiation has been demonstrated to alter Wnt/β-catenin signaling, as well as the proteasomal pathway involved in the degradation of the signaling components and thus regulation of β-catenin. The current review discusses recent progresses in our understanding of colorectal carcinogenesis in relation to different types of radiation and roles that radiation quality plays in deregulating β-catenin and ubiquitin-proteasome pathway (UPP) for colorectal cancer initiation and progression.
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Affiliation(s)
- Kamal Datta
- 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC USA
| | - Shubhankar Suman
- 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC USA
| | - Santosh Kumar
- 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC USA
| | - Albert J Fornace
- 1. Department of Biochemistry and Molecular & Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC USA.; 2. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia
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48
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Shirazi-Fard Y, Alwood JS, Schreurs AS, Castillo AB, Globus RK. Mechanical loading causes site-specific anabolic effects on bone following exposure to ionizing radiation. Bone 2015; 81:260-269. [PMID: 26191778 DOI: 10.1016/j.bone.2015.07.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 07/03/2015] [Accepted: 07/15/2015] [Indexed: 12/17/2022]
Abstract
During spaceflight, astronauts will be exposed to a complex mixture of ionizing radiation that poses a risk to their health. Exposure of rodents to ionizing radiation on Earth causes bone loss and increases osteoclasts in cancellous tissue, but also may cause persistent damage to stem cells and osteoprogenitors. We hypothesized that ionizing radiation damages skeletal tissue despite a prolonged recovery period, and depletes the ability of cells in the osteoblast lineage to respond at a later time. The goal of the current study was to test if irradiation prevents bone accrual and bone formation induced by an anabolic mechanical stimulus. Tibial axial compression was used as an anabolic stimulus after irradiation with heavy ions. Mice (male, C57BL/6J, 16 weeks) were exposed to high atomic number, high energy (HZE) iron ions ((56)Fe, 2 Gy, 600 MeV/ion) (IR, n=5) or sham-irradiated (Sham, n=5). In vivo axial loading was initiated 5 months post-irradiation; right tibiae in anesthetized mice were subjected to an established protocol known to stimulate bone formation (cyclic 9N compressive pulse, 60 cycles/day, 3 day/wk for 4 weeks). In vivo data showed no difference due to irradiation in the apparent stiffness of the lower limb at the initiation of the axial loading regimen. Axial loading increased cancellous bone volume by microcomputed tomography and bone formation rate by histomorphometry in both sham and irradiated animals, with a main effect of axial loading determined by two-factor ANOVA with repeated measure. There were no effects of radiation in cancellous bone microarchitecture and indices of bone formation. At the tibia diaphysis, results also revealed a main effect of axial loading on structure. Furthermore, irradiation prevented axial loading-induced stimulation of bone formation rate at the periosteal surface of cortical tissue. In summary, axial loading stimulated the net accrual of cancellous and cortical mass and increased cancellous bone formation rate despite prior exposure to ionizing radiation, in this case, HZE particles. Our findings suggest that mechanical stimuli may prove an effective treatment to improve skeletal structure following exposure to ionizing radiation.
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Affiliation(s)
- Yasaman Shirazi-Fard
- Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Joshua S Alwood
- Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Ann-Sofie Schreurs
- Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
| | - Alesha B Castillo
- Department of Mechanical and Aerospace Engineering, New York University, New York, NY, USA.
| | - Ruth K Globus
- Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA.
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49
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Allen AR, Raber J, Chakraborti A, Sharma S, Fike JR. 56Fe Irradiation Alters Spine Density and Dendritic Complexity in the Mouse Hippocampus. Radiat Res 2015; 184:586-94. [DOI: 10.1667/rr14103.1] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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50
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Walb MC, Black PJ, Payne VS, Munley MT, Willey JS. A reproducible radiation delivery method for unanesthetized rodents during periods of hind limb unloading. LIFE SCIENCES IN SPACE RESEARCH 2015; 6:10-4. [PMID: 26097807 PMCID: PMC4470431 DOI: 10.1016/j.lssr.2015.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm×30.5 cm×40.6 cm30.5 cm×30.5 cm×40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five centimeters of water-equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight-relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINACs at academic medical centers and the reliability of their dosimetry properties, this method may find great utility in the implementation of future ground-based studies that examine the combined spaceflight challenges of reduced loading and radiation while using the HLU rodent model.
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