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.
Related URLs:
http://www.ncbi.nlm.nih.gov/pubmed/26318907
Research Containing: Osteoprotegerin
SPACEFLIGHT AND HINDLIMB SUSPENSION DISUSE MODELS IN MICE
Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and increased susceptibility to fractures. The microgravity of space creates an extreme environment that provides a model for osteoporosis in humans. This greatly accelerated form of osteopenia results in a 0.5-2% loss of bone mass per month. Rat models for this osteoporosis have been examined on many occasions, but STS-108 was the first Space Shuttle flight to use mice. Data reported to date indicate that spaceflight experiments with mice hold promise in predicting some spaceflight effects on humans. Due to the cost and infrequency of flights, ground-based models have been developed to mimic the deleterious effects of the microgravity environment. Hindlimb suspension is one such localized model. This model removes gravitational loading from the hindlimbs by suspending the animal by its tail to a guy wire that runs lengthwise across the cage. Because mice had not flown before STS-108, a direct comparison of this model’s ability to predict spaceflight results has not been examined. The objective of this research is to closely repeat the STS- 108 profile, with hindlimb suspension replacing spaceflight. This includes examining the ability of the protein osteoprotegerin, an osteoclast-inhibiting therapeutic, to mitigate the deleterious effects of skeletal unloading. It is expected that the results will lead to better understanding of the mechanisms of mineralization and bone remodeling to aid in development of countermeasures to prevent spaceflight induced osteoporosis and aid the treatment of osteoporosis here on earth.
Related URLs:
https://www.researchgate.net/publication/8571784_Spaceflight_and_hindlimb_suspension_disuse_models_in_mice
MOLECULAR THERAPIES FOR DISUSE OSTEOPOROSIS
Microgravity causes changes in physiological systems that are both detrimental to human health and valuable for biomedical research. Some of the most pronounced and long-term changes occur in skeletal tissue, which experiences a profound and rapid wasting. Finding a countermeasure to the bone atrophy associated with weightlessness is necessary before long-duration human space exploration can be possible. However, these physiological changes can also be exploited as a biomedical model for osteoporosis, offering an extreme environment in which therapeutics can be tested and mechanisms examined. Utilizing space as a biomedical test-bed has been done on several flights: STS-41, 52, 57, 60, 62, 63, 77 and 108, the aims and results of which will be briefly summarized. The rational for spaceflight serving as a biomedical test-bed is that microgravity exposure (and resulting changes in the spacecraft environment) causes an accelerated model for biomedical disorders experienced, often as a result of the normal aging process, here on Earth. The most common target system for these flights was skeletal, with the goal of mimicking osteoporosis, but immune dysfunction, wound healing and muscle atrophy were also studied. Most recently (STS-108, December 2001), the biotechnology company Amgen examined the ability of osteoprotegerin (OPG) to mitigate the osteoporosis caused by microgravity. OPG is a protein that is critical to the differentiation and activation of bone resorbing osteoclasts. Amgen is developing OPG as a treatment for osteoporosis and the bone loss associated with metastatic bone cancer. Over the 12-day flight, the mice experienced a decline in bone strength (15-20% relative to ground controls) that was greater than that of ground-based disuse models. The mechanical testing data was complimented by serum, 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 the increase in resorption and maintaining mineralization.
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