Commercial Biomedical Testing Module-3: Assessment of sclerostin antibody as a novel bone forming agent for prevention of spaceflight-induced skeletal fragility in mice (CBTM-3-Sclerostin Antibody) - 08.27.15

Overview | Description | Applications | Operations | Results | Publications | Imagery

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Science Objectives for Everyone
Commercial Biomedical Testing Module-3: Assessment of sclerostin antibody as a novel bone forming agent for prevention of spaceflight-induced skeletal fragility in mice (CBTM-3-Sclerostin Antibody) is one in a series of investigations designed to determine if administering an experimental agent preflight reduces the loss of bone associated with space flight. Humans and animals have been observed to lose bone mass during the reduced gravity of space flight. The sclerostin antibody is designed to inhibit the action of "sclerostin", a protein that is a key negative regulator of bone formation, bone mass and bone strength.
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Information Pending

The following content was provided by Chris Paszty, Ph.D., Louis S. Stodieck, Ph.D., Hua Zhu (David) Ke, M.D., Martyn Robinson, PhD., Virginia L. Ferguson, Ph.D., Mary L. Bouxsein, Ph.D., Ted A. Bateman, Ph.D., and is maintained in a database by the ISS Program Science Office.
Experiment Details

OpNom:

Principal Investigator(s)
Chris Paszty, Ph.D., Amgen, Inc., Thousand Oaks, CA, United States
Louis S. Stodieck, Ph.D., University of Colorado, BioServe Space Technologies, Boulder, CO, United States
Hua Zhu (David) Ke, M.D., Thousand Oaks, CA, United States
Martyn Robinson, PhD., UCB in Brussels, Brussels, Belgium
Virginia L. Ferguson, Ph.D., University of Colorado, Boulder, CO, United States
Mary L. Bouxsein, Ph.D., Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States
Ted A. Bateman, Ph.D., University of North Carolina, Chapel Hill, NC, United States

Co-Investigator(s)/Collaborator(s)
Information Pending

Developer(s)
Amgen Research, Thousand Oaks, CA, United States
BioServe Space Technologies, University of Colorado, Boulder, CO, United States
NASA Ames Research Center, Moffett Field, CA, United States

Sponsoring Space Agency
National Aeronautics and Space Administration (NASA)

Sponsoring Organization
National Laboratory (NL)

Research Benefits
Information Pending

ISS Expedition Duration 1
March 2011 - September 2011

Expeditions Assigned
27/28

Previous ISS Missions
A similar investigation, CBTM, flew round trip to the ISS on STS-108 during ISS Expedition 4. CBTM-2 flew round trip to the ISS on STS-118 during ISS Expedition 15. AEMs have flown on numerous space shuttle missions over the years.

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Experiment Description

Research Overview

  • The loss of bone mass during space flight remains a significant problem for human space missions, especially long-duration space flights. Varieties of countermeasures have been tried, mostly based on exercise, but have not proven to be totally effective in reducing bone loss.


  • Commercial Biomedical Testing Module-3: Assessment of sclerostin antibody as a novel bone forming agent for prevention of spaceflight-induced skeletal fragility in mice (CBTM-3-Sclerostin Antibody) is an investigation focusing on a novel experimental agent. The agent is an antibody against the protein, sclerostin, a protein that is known to inhibit bone formation. If the agent is effective in reducing or preventing bone loss in mice during the flight, then it will demonstrate the potential for pharmacologic inhibition of sclerostin to be further tested for use in astronauts and in patients under disuse conditions. A different sclerostin antibody than the one being used for this STS-135 mouse study is currently in clinical trials as a collaboration between Amgen Inc. and UCB.

Description
Commercial Biomedical Testing Module-3: Assessment of sclerostin antibody as a novel bone forming agent for prevention of spaceflight-induced skeletal fragility in mice (CBTM-3-Sclerostin Antibody) is part of a suite of investigations studying the ability of novel experimental agents to prevent disuse induced bone loss, and extend current knowledge about the effects of microgravity on the musculoskeletal system and the ability of a ground-based analog system (rodent hind limb suspension) to reproduce those effects in mice. The ultimate objective is to mitigate the risk for space-induced skeletal fragility associated with missions to low Earth orbit, and exploration destinations. If the sclerostin antibody proves successful in reducing space flight induced bone mass loss in mice, then it will demonstrate the potential for pharmacologic inhibition of sclerostin to be used in astronauts. Beyond the perils of microgravity, the findings may also provide novel insight into prevention and treatment of the skeletal fragility that can result from “skeletal disuse” in such conditions as immobilization, stroke, cerebral palsy, muscular dystrophy, spinal cord injury, and reduced physical activity. Eight to ten mice are flown in each of three Animal Enclosure Modules (AEMs) (http://flighthardware-spacebiosciences.arc.nasa.gov/) located on the space shuttle middeck. Half of the mice are given a preflight injection of a novel experimental bone forming agent, an antibody designed to inhibit the activity of the protein “sclerostin”. The remaining mice receive a placebo. Following the flight, a team of scientists, are studying various aspects of the structure, composition, strength, and cell and molecular nature of the bones from the flight and ground-based control mice. Bones from mice receiving the bone forming agent are compared to those receiving the placebo and are also compared to a ground control group, i.e., mice that were housed in AEM's on the ground during the flight.

This research is also expected to contribute data to the current body of research on microgravity effects on the skeletal, cardiovascular, and immune systems, liver and kidney function as well as other physiological systems through a tissue sharing program. Every effort will be made to harvest as many different samples and types of tissue from the mice as possible for other mission specific biomedical research. Positive results from this research may advance our understanding of mechanistic changes that occur in various physiological systems after exposure to microgravity and support overall efforts to reduce health risks to crewmembers. The investigations resulting from the CBTM-3 tissue sharing program are as follows:

  • Brain
    • Alan R. Hargens, University of California San Diego, La Jolla CA
    • Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
    • Gregory A. Nelson, Ph.D. , Loma Linda University, Loma Linda, CA
    • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
  • Eyes
    • Susana B. Zanello, Ph.D., Universities Space Research Association, Houston, TX
    • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
  • Lung
    • Roberto Garofalo, M.D., University of Texas Medical Branch, Galveston, TX
    • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
  • Kidneys and Small Intestine
    • Moshe Levi, University of Colorado, Denver, CO
  • Liver
    • Karen Jonscher, Ph.D.,  University of Colorado, Denver CO
    • Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
    • Jian Tian, Ph.D., Loma Linda University, Loma Linda, CA
    • Scott  M. Smith, Ph.D., Johnson Space Center, Houston, TX
    • Virginia E. Wotring, Ph.D., Universities Space Research Association, Houston, TX
  • Metatarsals
    • Eduardo Almeida, Ph.D.,  Ames Research Center, Moffett Field, CA
  • Distal Tibia and Tarsus
    • Hiroki Yokota, Ph.D., Indiana University-Purdue University Indianapolis, Indianapolis, IN
  • Thymus
    • Millie Hughes-Fulford, Ph.D.,  University of California, San Francisco, San Francisco, CA
    • Daila S. Gridley, Loma Linda University, Loma Linda, CA
  • Spleen
    • Millie Hughes-Fulford, Ph.D.,  University of California, San Francisco, San Francisco, CA
    • Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
  • Extensor digitorum longus, transversus abdominis and masseter muscle
    • Elisabeth R. Barton, Ph.D., University of Pennsylvania, Philadelphia, PA
  • Temporal Bones
    • Richard D. Boyle, Ph.D., Universities Space Research Association, Moffett Field, CA
    • Larry F. Hoffman, Ph.D.,  University of California Los Angeles, Los Angeles, CA
    • Shin-ichi Usami, M.D., Shinshu University, Matsumoto, Japan
  • Cerebral Artery, Mesenteric Vein, Heart, Soleus
    • Michael D. Delp, Ph.D.,  University of Florida, Gainesville, FL
  • Adrenals
  •     Michael Pecaut, Ph.D, Loma Linda University, Loma Linda, CA
  • Femoral Heads, Quadriceps and Skin
    • David Fitzgerald, Ph.D.,  Oregon Health and Science University, Portland, OR
  • Tail
    • Alan R. Hargens, University of California San Diego, La Jolla CA
  • Heart, Soleus, Extensor digitoum longus and transversus abdominis
    • Brooke C. Harrison, Ph.D., University of Colorado, Boulder, CO
  • Biceps brachii and Triceps brachi
    • Akihiko Ishihara, Ph.D.,  Kyoto University, Kyoto, Japan
  • Skin
    • Xiao Wen Mao, M.D., Loma Linda University, Loma Linda, CA
    • Masahiro Terada, Japan Aerospace Exploration Agency, Tsukuba, Japan
  • Uterine horn, ovaries, stomach
    • Joseph S. Tash, Ph.D., University of Kansas Medical Center, Kansas City, KS
  • Distal Colon and Fecal Pellets
    • Scott  M. Smith, Ph.D., Johnson Space Center, Houston, TX
  • Salivary glands and 1/4 the left ventricle
    • Maija Mednieks, Ph.D., University of Connecticut Health Center, Farmington, CT
  • Humerus, rotator cuff, scapula units  and Achilles tendon calcaneus units
    • Stavros Thomopoulos, Ph.D., Washington University, St. Louis, MO
  • Meniscus
    • Jeffrey Willey, Ph.D.,  Wake Forest School of Medicine, Winston-Salem, NC

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Applications

Space Applications
If the novel bone forming agent proves successful in mitigating bone mass loss in-flight, this would demonstrate the potential application of pharmacologic sclerostin inhibition as a countermeasure for use in long-duration human space flight missions.

Earth Applications
If the sclerostin antibody proves successful in reducing space flight induced bone mass loss, the results may point towards possible prevention and treatment of the bone loss that can result from “skeletal disuse” in such conditions as immobilization, stroke, cerebral palsy, muscular dystrophy, spinal cord injury, and reduced physical activity.

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Operations

Operational Requirements
AEM's with eight to ten mice each are requested for a late load (Launch minus 72 to 24 hours) and to be removed postflight within four hours of landing. During flight the crew is requested to conduct a daily health check of the mice, i.e., a visual observation through the Lexan lid of the AEMs. Unusual appearances of the mice are to be reported as soon as possible.

Operational Protocols
For this study nine week old female C57BL/6 mice are launched on the space shuttle. Flight mice are treated once with a placebo vehicle or the bone forming agent approximately 24 hours before launch. Ground control mice are treated in the same manner but with a 48 hour offset. Ground control mice are housed under the same environmental conditions (temperature, light/dark cycle, humidity, oxygen levels and carbon dioxide levels) as the flight mice. All mice receive the same full access to food and water. Upon return to Earth, the AEMs are returned to the research team for analysis. Body weight is also measured preflight and postflight. Statistical comparisons will be made between the treated and control mice.

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Results/More Information

Information Pending

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Results Publications

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Ground Based Results Publications

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ISS Patents

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Related Publications

    Ellman R, Spatz JM, Cloutier AM, Palme R, Christiansen BA, Bouxsein ML.  Partial reductions in mechanical loading yield proportional changes in bone density, bone architecture, and muscle mass. Journal of Bone and Mineral Research. 2013 April; 28(4): 875-885. DOI: 10.1002/jbmr.1814. PMID: 23165526.

    Spatz JM, Fields EE, Yu EW, Pajevic PD, Bouxsein ML, Sibonga JD, Zwart SR, Smith SM.  Serum sclerostin increases in healthy adult men during bed rest. Journal of Clinical Endocrinology and Metabolism. 2012 September; 97(9): E1736-1740. DOI: 10.1210/jc.2012-1579. PMID: 22767636.

    Wagner EB, Granzella NP, Saito H, Newman DJ, Young LR, Bouxsein ML.  Partial weight suspension: a novel murine model for investigating adaptation to reduced musculoskeletal loading. Journal of Applied Physiology. 2010 August; 109(2): 350-357. DOI: 10.1152/japplphysiol.00014.2009. PMID: 20522735.

    Jee WS.  Anti-sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. Journal of Bone and Mineral Research. 2008; 23(1): S40.

    Spatz JM, Ellman R, Cloutier AM, Louis L, van Vliet M, Suva LJ, Dwyer D, Stolina M, Ke HZ, Bouxsein ML.  Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. Journal of Bone and Mineral Research. 2013 April; 28(4): 865-874. DOI: 10.1002/jbmr.1807. PMID: 23109229.

    Ferguson VL, Ayers RA, Bateman TA, Simske SJ.  Bone development and age-related bone loss in male C57BL/6J mice. Bone. 2003; 33(3): 387-398.

    Fajardo RJ, Manoharan RK, Pearsall RS, Davies MV, Marvell T, Monnell TE, Ucran JA, Pearsall AE, Khanzode D, Kumar R, Underwood KW, Roberts B, Seehra J, Bouxsein ML.  Treatment with a soluble receptor for activin improves bone mass and structure in the axial and apendicular skeleton of female cynomolgus macaques (Macaca fascicularis). Bone. 2010; 46(1): 64-71.

    Devlin MJ, Cloutier AM, Thomas NA, Panus DA, Lotinun S, Pinz I, Baron R, Rosen CJ, Bouxsein ML.  Caloric restriction leads to high marrow adiposity and low bone mass in growing mice. Journal of Bone and Mineral Research. 2010; 25(9): 2078-88.

    O-Brien CA, Plotkin LI, Galli C, Goellner JJ, Gortazar AR, Allen MR, Robling AG, Bouxsein ML, Schipani E, Turner CH, Jilka RL, Weinstein RS, Manolagas SC, Bellido T.  Control of bone mass and remodeling by PTH receptor signaling in osteocytes. PLOS ONE. 2008; 3(8): 2942.

    Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, Li Y, Feng G, Gao X, He L.  Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. Journal of Bone and Mineral Research. 2009 Oct; 24(10): 1651-1661. DOI: 10.1359/jbmr.090411. PMID: 19419300.

    Liu X, Bruxvoort KJ, Zylstra CR, Liu J, Cichowski R, Faugere M, Bouxsein ML, Wan C, Williams BO, Clemens TL.  Lifelong accumulation of bone in mice lacking Pten in osteoblasts. Proceedings of the National Academy of Sciences of the United States of America. 2007; 104(7): 2259-64.

    Lang TF, LeBlanc AD, Evans HJ, Lu Y, Genant HK, Yu A.  Cortical and Trabecular Bone Mineral Loss from the Spine and Hip in Long-duration Spaceflight. Journal of Bone and Mineral Research. 2004; 19(6): 1006-1012. DOI: 10.1359/JBMR.040307.

    Li X.  Inhibition of sclerostin by monoclonal antibody increases bone formation, bone mass, and bone strength in aged male rats. Journal of Bone and Mineral Research. 2010; 25(12): 2647-2656.

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Related Websites
BioServe
Space Biosciences Division

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Imagery

image NASA Image: S118E09327 - STS-118 Mission Specialist Tracy Caldwell and Pilot Charles Hobaugh observing the Animal Enclosure Modules (AEMs) in the Middeck of the Space Shuttle Endeavour.
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image Animal Enclosure Modules (AEMs) from NASA Ames Research Center. Image courtesy of NASA.
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