title: Simulating the Lunar Environment: Partial Weightbearing and High-LET Radiation-Induce Bone Loss and Increase Sclerostin-Positive Osteocytes.
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.
authors.affiliation: a   Health and Kinesiology.
authors.forename: B R
authors.initials: BR
authors.lastname: Macias
authors.affiliation: a   Health and Kinesiology.
authors.forename: F
authors.initials: F
authors.lastname: Lima
authors.affiliation: a   Health and Kinesiology.
authors.forename: J M
authors.initials: JM
authors.lastname: Swift
authors.affiliation: b   Biomedical Engineering.
authors.forename: Y
authors.initials: Y
authors.lastname: Shirazi-Fard
authors.affiliation: a   Health and Kinesiology.
authors.forename: E S
authors.initials: ES
authors.lastname: Greene
authors.affiliation: g   Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: M R
authors.initials: MR
authors.lastname: Allen
authors.affiliation: a   Health and Kinesiology.
authors.forename: J
authors.initials: J
authors.lastname: Fluckey
authors.affiliation: b   Biomedical Engineering.|c   Mechanical Engineering.
authors.forename: H A
authors.initials: HA
authors.lastname: Hogan
authors.affiliation: e   Nuclear Engineering and.
authors.forename: L
authors.initials: L
authors.lastname: Braby
authors.affiliation: f   Statistics, Texas A&M University, College Station, Texas, 77843 and.
authors.forename: Suojin
authors.initials: S
authors.lastname: Wang
authors.affiliation: a   Health and Kinesiology.|d   Intercollegiate Faculty of Nutrition.
authors.forename: S A
authors.initials: SA
authors.lastname: Bloomfield
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000528:radiation effects; D001862:Bone Resorption / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003359:Cosmic Radiation / Q000009:adverse effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005269:Femur / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D006023:Glycoproteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D018499:Linear Energy Transfer; D051379:Mice; D016081:Moon; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D016474:Weight-Bearing; D018474:Weightlessness Simulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse