title: Mechanical loading causes site-specific anabolic effects on bone following exposure to ionizing radiation.
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.
authors.affiliation: Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA. Electronic address: Yasaman.Shirazi-Fard@nasa.gov.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Shirazi-Fard
authors.affiliation: Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA. Electronic address: joshua.s.alwood@nasa.gov.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Alwood
authors.affiliation: Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA. Electronic address: ann-sofie.schreurs@nasa.gov.
authors.forename: Ann-Sofie
authors.initials: AS
authors.lastname: Schreurs
authors.affiliation: Department of Mechanical and Aerospace Engineering, New York University, New York, NY, USA. Electronic address: alesha.castillo@nyu.edu.
authors.forename: Alesha B
authors.initials: AB
authors.lastname: Castillo
authors.affiliation: Bone and Signaling Laboratory, Space Biosciences Division, NASA Ames Research Center, Mail-Stop 236-7, Moffett Field, CA 94035, USA. Electronic address: ruth.k.globus@nasa.gov.
authors.forename: Ruth K
authors.initials: RK
authors.lastname: Globus
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D008660:Metabolism / Q000502:physiology* / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D010012:Osteogenesis / Q000502:physiology* / Q000528:radiation effects*; D011839:Radiation, Ionizing; D013977:Tibia / Q000378:metabolism / Q000528:radiation effects; D016474:Weight-Bearing / Q000502:physiology*
keywords: Bone marrow; Cancellous bone microarchitecture; Cortical bone; Histomorphometry; Ionizing radiation; Mechanical loading; Osteoprogenitor; Spaceflight; Stem cells