title: Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice.
abstract: Bone loss associated with microgravity exposure poses a significant barrier to long-duration spaceflight. Osteoprotegerin-Fc (OPG-Fc) is a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor that causes sustained inhibition of bone resorption after a single subcutaneous injection. We tested the ability of OPG-Fc to preserve bone mass during 12 days of spaceflight (SF). 64-day-old female C57BL/6J mice (n=12/group) were injected subcutaneously with OPG-Fc (20mg/kg) or an inert vehicle (VEH), 24h prior to launch. Ground control (GC) mice (VEH or OPG-Fc) were maintained under environmental conditions that mimicked those in the space shuttle middeck. Age-matched baseline (BL) controls were sacrificed at launch. GC/VEH, but not SF/VEH mice, gained tibia BMD and trabecular volume fraction (BV/TV) during the mission (P<0.05 vs. BL). SF/VEH mice had lower BV/TV vs. GC/VEH mice, while SF/OPG-Fc mice had greater BV/TV than SF/VEH or GC/VEH. SF reduced femur elastic and maximum strength in VEH mice, with OPG-Fc increasing elastic strength in SF mice. Serum TRAP5b was elevated in SF/VEH mice vs. GC/VEH mice. Conversely, SF/OPG-Fc mice had lower TRAP5b levels, suggesting that OPG-Fc preserved bone during spaceflight via inhibition of osteoclast-mediated bone resorption. Decreased bone formation also contributed to the observed osteopenia, based on the reduced femur periosteal bone formation rate and serum osteocalcin level. Overall, these observations suggest that the beneficial effects of OPG-Fc during SF are primarily due to dramatic and sustained suppression of bone resorption. In growing mice, this effect appears to compensate for the SF-related inhibition of bone formation, while preventing any SF-related increase in bone resorption. We have demonstrated that the young mouse is an appropriate new model for SF-induced osteopenia, and that a single pre-flight treatment with OPG-Fc can effectively prevent the deleterious effects of SF on mouse bone.
authors: Department of Orthopaedics and Rehabilitation, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors: Shane A
authors: SA
authors: Lloyd
authors: Metabolic Disorders, Amgen Incorporated, Thousand Oaks, CA 91320, United States.
authors: Sean E
authors: SE
authors: Morony
authors: BioServe Space Technologies, Department of Aerospace Engineering and Science, University of Colorado Boulder, CO 80309, United States; Department of Mechanical Engineering, University of Colorado Boulder, CO 80309, United States.
authors: Virginia L
authors: VL
authors: Ferguson
authors: BioServe Space Technologies, Department of Aerospace Engineering and Science, University of Colorado Boulder, CO 80309, United States; Hewlett-Packard Labs Fort Collins, CO 80528, United States.
authors: Steven J
authors: SJ
authors: Simske
authors: BioServe Space Technologies, Department of Aerospace Engineering and Science, University of Colorado Boulder, CO 80309, United States.
authors: Louis S
authors: LS
authors: Stodieck
authors: Metabolic Disorders, Amgen Incorporated, Thousand Oaks, CA 91320, United States.
authors: Kelly S
authors: KS
authors: Warmington
authors: Departments of Biomedical Engineering and Radiation Oncology, University of North Carolina, Chapel Hill, NC 27599, United States.
authors: Eric W
authors: EW
authors: Livingston
authors: Metabolic Disorders, Amgen Incorporated, Thousand Oaks, CA 91320, United States.
authors: David L
authors: DL
authors: Lacey
authors: Metabolic Disorders, Amgen Incorporated, Thousand Oaks, CA 91320, United States.
authors: Paul J
authors: PJ
authors: Kostenuik
authors: BioServe Space Technologies, Department of Aerospace Engineering and Science, University of Colorado Boulder, CO 80309, United States; Departments of Biomedical Engineering and Radiation Oncology, University of North Carolina, Chapel Hill, NC 27599, United States. Electronic address: bateman@unc.edu.
authors: Ted A
authors: TA
authors: Bateman
mesh_terms: D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015675:Osteocalcin / Q000097:blood; D053244:Osteoprotegerin / Q000494:pharmacology*; D053245:RANK Ligand / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013026:Space Flight; D014893:Weightlessness / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D007141:Immunoglobulin Fc Fragments; C000608353:OPG-Fc fusion protein, rat; D053244:Osteoprotegerin; D053245:RANK Ligand; D011993:Recombinant Fusion Proteins; C505689:Tnfsf11 protein, mouse; D015675:Osteocalcin; D000469:Alkaline Phosphatase
keywords: Bone loss; Countermeasure; Mice; Osteoprotegerin; Spaceflight