MOLECULAR THERAPIES FOR DISUSE OSTEOPOROSIS
Abstract
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.
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.