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Commercial Biomedical Testing Module: Effects of Osteoprotegerin on Bone Maintenance in Microgravity (CBTM)
03.23.09

Overview | Description | Applications | Operations | Results | Publications | Images

Experiment/Payload Overview

Brief Summary

Provided the capability to use the microgravity environment for evaluation of new pharmaceutical candidates in small mammals. Results may expedite the review of new pharmaceuticals for allowing immediate access to new disease treatments.

Principal Investigator

  • Ted A. Bateman, Ph.D., Clemson University, Clemson, SC

    • Co-Investigator(s)/Collaborator(s)

  • Paul Kostenuik, Amgen, Thousand Oaks, CA

    • Payload Developer


    BioServe Space Technologies, University of Colorado, Boulder, CO

    Sponsoring Agency

    National Aeronautics and Space Administration (NASA)

    Expeditions Assigned

    |4|

    Previous ISS Missions

    Similiar investigations to CBTM were conducted on STS-60, STS-63 and STS-77 as Immune-01, Immune-02 and Immune-03, respectively.

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    Experiment/Payload Description

    Research Summary

    • The CBTM was flown to help determine the efficacy of the novel protein osteoprotegerin in a complete unloading environment and examining spaceflight as a unique pre-clinical model for osteoporosis. Osteoprotegerin is a recently discovered, naturally circulating protein that increases bone density by inhibiting bone resorption.


    • Osteoporosis is a debilitating disease that afflicts millions of people worldwide. One of the physiological changes experienced by astronauts during space flight is the accelerated loss of bone mass due to the lack of gravitational loading on the skeleton. This bone loss experienced by astronauts is similar to osteoporosis in the elderly population. Osteoprotegerin (OPG), a bone metabolism regulator, is being considered by the Food and Drug Administration (FDA) as a new treatment for osteoporosis.


    • Laboratory mice were treated with either OPG or a placebo before launch of Expedition 4. The mice were housed in a animal enclosure module designed specifically for space flight. This experiment will provide a preclinical trial model to determine the effectiveness of OPG to treat bone loss.

    Description

    Osteoporosis is a debilitating disease that afflicts millions worldwide. One of the physiological changes experienced by space crews during space flight is the accelerated loss of bone mass due to the lack of gravitational loading on the skeleton, a loss that is similar to that experienced by the elderly population on Earth. Osteoprotegerin (OPG), which is a bone metabolism regulator, is being evaluated by the Food and Drug Administration (FDA) as a new treatment for osteoporosis.

    The Commercial Biomedical Testing Module (CBTM) examined the effects of OPG on bone maintenance in space using aged mice (older than nine months) as test subjects. The bone changes observed in older mice more closely reflect the bone changes observed in older humans. The mice were housed in three animal enclosure modules (AEMs), which provide the animal subjects with everything necessary to maintain health. Half of the mice were treated with OPG, a novel protein that regulates bone resorption, and half were treated with a placebo.

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    Applications

    Space Applications

    Astronauts suffer from a significant loss of bone mass during space flight, the ISS Medical Project office has developed some countermeasures to hinder the rapid loss of bone mass. Despite these countermeasures bone mass loss continues to be a problem for astronauts. Finding additional countermeasures will increase the overall health of astronauts on long duration missions.

    Earth Applications

    In microgravity, the messages received by the osteoblasts and osteoclasts are altered. Specifically, without the stresses caused by the Earth's gravitational pull, osteoclasts remove more bone and osteoblasts deposit less new bone. Understanding how these signals change and how OPG mitigates these changes will give scientists insight in how to fight bone loss in astronauts during long duration space flight and in osteoporosis patients on Earth.

    Osteoporosis is a major public health threat for an estimated 44 million people worldwide. Space flight induces a systematic, accelerated bone loss, hence, this investigation will provide a good model for osteoporosis and potential treatments. It will provide scientists further insight into skeletal loss from microgravity and the role of OPG as a potential treatment for osteoporosis.

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    Operations

    Operational Requirements

    CBTM is a sortie, meaning that CBTM will launch and return on STS-108. The AEMs require power from an external source to operate the fans and lighting, but no computer support is needed. Crew interaction is minimal.

    Operational Protocols

    During the flight, crew will check the AEMs daily to make sure the equipment is functioning nominally and to make sure there is water in the Water Refill Box. The crew will probably need to add more water, using the water refill line, three times during the flight. After the flight, the AEMs will be returned to the research team.

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    Results/More Information

    During ISS Expedition 4, 24 female mice were flown to ISS on shuttle flight STS-108 in three AEMs. The AEMs remained on STS-108 throughout the 12-day mission.

    Mice exposed to microgravity exhibited a 15 - 20 percent decline in femur elastic strength and a 40 - 60 percent decrease in bone formation when compared to the controls. The femur elastic strength decline was caused by three mechanisms: reduced bone formation, increased bone resorption, and inhibition of mineralization. Mice exposed to microgravity treated with OPG exhibited no discernable decline in femur elastic strength, and bone resorption was significantly increased (Bateman 2004). Mechanical testing data were complimented by serum, messenger ribonucleic acid (mRNA), and histological analyses that indicated a decline in bone formation and an increase in bone resorption in addition to an inhibition of mineralization. OPG mitigated the decline in mechanical strength by preventing increase in resorption and maintaining mineralization. In addition to this detailed analysis of skeletal properties, a secondary analysis of calf muscles from placebo-treated specimens was performed to collect baseline data to validate space-flown mice as an appropriate model for sarcopenia (age-related muscle loss). Space flight caused a 15 - 30 percent decline in muscle fiber diameter size compared to appropriate ground controls (Harrison et al. 2003).

    Data obtained from the mice following return to Earth indicated some alternations in immune functions. Analysis of the spleenocytes (immune cells produced by the spleen) indicated an increase in B-cell (white blood cell that matures in the bone marrow and, when stimulated by an antigen, differentiates into plasma cells) production compared to T-cells (white blood cells that complete maturation in the thymus and have various roles in the immune system). A slightly lower white blood-cell count in the flight animals compared to the controls was not statistically significant. The spleen mass was 18 - 28 percent lower in flight mice compared to controls. Results also indicated that flight mice weighed 10 - 12 percent less than ground controls (Pecaut et al. 2003).

    The ability to survive a major physical trauma in microgravity may be compromised due to an altered immune system. Platelets (constituent of blood that promotes clotting at the site of injury) are the primary cells involved in the wound healing process. The animals studied had significantly higher platelet levels but low volume compared to the controls. This indicates that the lack of platelets in the wound healing process is not a problem, but that platelets formed in microgravity have a decreased functionality in the wound healing process. Data indicated that a short stay in microgravity can induce significant changes in immune defense mechanisms, hematopoiesis (blood cell formation), and other aspects of health (Gridley et al. 2003).

    Analysis of microarray data revealed that 272 mRNAs were significantly altered by space flight, the majority of which displayed similar responses to hindlimb suspension, while reloading tended to counteract these responses. Several mRNAs altered by space flight were associated with muscle growth, including the PI3 kinase regulatory subunit p85 alpha, insulin response substrate-1, the forkhead box O1 transcription factor, and MAFbx/atrogin1. Moreover, myostatin mRNA expression tended to increase while mRNA levels of the myostatin inhibitor FSTL3 tended to decrease in response to space flight. In addition, mRNA levels of the slow-oxidative fiber associated transcriptional co-activator peroxisome proliferator associated receptor-(PPAR) gamma coactivator-1alpha and the transcription factor PPAR-alpha were significantly decreased in space flight gastrocnemius. Finally, space flight resulted in a significant decrease in levels of the microRNA miR-206. Together these data demonstrate that space flight induces significant changes in mRNA expression of genes associated with muscle growth and fiber type (Allen et al. 2008).

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    Related Web Sites
  • NASA Fact Sheet
  • BioServe Space Technologies

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    Publications

    Results Publications

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      Related Publications
      • Sieck GC. Commentary. Journal of Applied Physiology. ;94:2084. 2003
      • Dalton P, Gould M, Girten B, Stodieck LS, Bateman TA Preventing annoyance from odors in spaceflight: a method for evaluating the sensory impact of rodent housing. Journal of Applied Physiology. ;95(5):2113-2121. 2003
      • Adams GR, Caiozzo VJ, Baldwin KM. Skeletal muscle unweighting: spaceflight and ground-based models. Journal of Applied Physiology ;95:2185-2201. 2003

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      Images

      imageFluorescent image of femur diaphysis from spaceflight placebo treated mouse, indicating greatly decreased bone formation (calcein label indicates where bone was forming at the time of launch, allowing quantification of bone formation rates during flight. Courtesy image from Marshall Space Center.
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      imageFluorescent image of femur diaphysis from ground control placebo treated mouse, indicating greatly decreased bone formation (calcein label indicates where bone was forming at the time of launch, allowing quantification of bone formation rates during flight. Courtesy image from Marshall Space Center.
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      imageImage on the left shows a microCT image of trabecular bone from proximal tibia from spaceflight mouse compared to ground control mouse on right. Courtesy image from Marshall Space Center.
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      imageBioServe Post-doctoral fellow and engineer, Ted Bateman (on left) and a NASA engineer (right) prepare CBTM for launch on board STS-108. Image courtesy of Marshall Space Center.
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      Information Provided and Updated by the ISS Program Scientist's Office
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