A Strategy for Research in Space Biology and Medicine in the New Century (1998) / Chapter Skim
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6 Bone Physiology
6 Bone Physiology
Pages 80-96
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From page 80... ...
, and the effects of hormones on this process. It summarizes current information on mechanical effects on bone, effects that may be the basis for the changes observed in microgravity or space environment conditions, briefly reviewing clinical observations; experiments on humans, animals, and cells; and putative mechanisms.
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From page 81... ...
There are fewer fluctuations in bone mass related to the other two functions, except during very active physiological or pathological hemopoiesis, when the marrow cavity expands at the expense of bone. The process of bone destruction and rebuilding is called remodeling.
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From page 82... ...
is remodeling. Bones, as well as other structures, are apparently unaffected when embryonic development of chicks occurs during microgravity in shuttle flights.2 Bones grow in length only at the cartilagenous epiphyses, where chondrocytes proliferate, differentiate, undergo hypertrophy, and mineralize the surrounding matrix on which the initial bone deposits, as described above for endochondral bone formation.
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From page 83... ...
In adults, GH or IGF- 1 stimulate both bone formation and bone resorption without increasing bone mass. In individuals with a GH deficiency, bone and muscle mass are reduced and have been reported to increase following GH administrations IGF-1 and IGF-2 have been extracted from bone, are made by bone cells, and were reported in experimental studies to stimulate osteoblast proliferation and collagen synthesis in vitro.
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From page 84... ...
MECHANICAL EFFECTS ON BONE REMODELING Clinical Observations and Human Experimentation Clinical observations and human experimentation show that human bone mass and structure are ideally suited to sustain the loads exerted upon them. There is well-documented bone loss after the removal of mechanical loading and somewhat more limited documentation of increased bone mass in response to mechanical stimulation.
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From page 85... ...
Within 2 weeks, these animals lose about 25 percent of their cancellous bone in the proximal tibia and show a 30 percent reduction in the mechanical strength of the shaft.26 27 Interestingly, recent studies have shown that hindlimb unloading causes a 40 percent reduction in blood flow in the unloaded extremities.28 Immobilization experiments conducted in dogs, whose cortical bone is more similar to that in humans, also showed bone loss, including significant reduction in the cancellous bone of the proximal radius of the immobilized dogs. There was significant recovery of bone following remobilization, except for the bone mineral density in the central radius.29 An interesting model is the disarticulated ulna of a turkey, which maintains its vascular supply but is totally unloaded.30 This bone is undergoing rapid resorption, which can be prevented with the amazingly limited mechanical stimulation of four Nine c,vo,l~,.~ nor Slav F'~rth~,r m~,c,hnnic,~1 Nine .~tim'~l~t~,.~ n~,rin.~t~,~1 hone, formation that depends D ~ r ~ D r on loading strain and frequency.3~ 32
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From page 86... ...
It was recently shown that bone loss caused by estrogen deficiency in rats is influenced by running treadmill exercises and functional unloading.34 Whether these findings extrapolate to humans remains to be seen. Putative Mechanisms
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From page 87... ...
The best documented is upregulation of prostaglandin release.4647 Inhibitors of prostaglandin synthesis block responses to mechanical stimulation;4849 prostaglandin E2 and I2 have been implicated.50 Other possible secondary responses include TGF,8 and IGF1, which increase bone formation and bone mass in unloaded bones in rats.5~ 52 Mechanical strain promotes release of FGF2 from vascular smooth muscle cells,53 and shear stress induces cyclooxygenase 2, as well as endothelial cell nitric oxide synthase and manganese superoxide dismutase in endothelial cells.54 In osteoblasts, shear stress also causes nitric oxide release.55 In addition, pulsating fluid flow was shown to stimulate prostaglandin release and cyclooxygenase 2 in mouse bone cells.56 G proteins and nitric oxide were also shown to mediate the response of bovine articular chondrocytes to shear stress.57 Another recently reported secondary response is the induction of the gene for the glutamate transporter,58 which is of interest because the glutamate receptor in C elegans has been implicated in tactile responses.59 MICROGRAVITY EFFECTS ON THE SKELETON Caveats More than 30 years of microgravity research has clearly established that the skeleton is one of the organs at risk (for a recent review see van Loon et al., 19936° )
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From page 88... ...
Major recurrent findings were a negative calcium balance and a decrease in bone mineral density (BMD)
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From page 89... ...
There is some evidence from a twins study suggesting that the vitamin D receptor gene may correlate with bone mineral density.68 69 Other polymorphisms that reportedly correlate with bone density or osteoporosis but have not been as extensively studied include collagen type I, estrogen receptor, and interleukin 1. There is also a report on familial high bone density, localized by linkage analysis to chromosome 11.
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From page 90... ...
Instrumentation that can be used for different types of mechanical stimulation should be developed and different types of exercise should be evaluated. Ground experiments suggest that impact loading is most elective in maintaining or increasing bone mass, and animal experiments suggest that short-duration mechanical stimulation may be sufficient to maintain bone mass in immobilized bones.
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From page 91... ...
Thus, examination of animal bones, primarily from rats exposed to microgravity for short durations (4 to 15 days) showed either no effect or a reduction in bone formation, relative to controls that were not always perfectly matched.
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From page 92... ...
Evaluate the interaction between osteoblast lineage cells and osteoclast precursors under microgravity conditions with l-g centrifuge controls, using the well-established ground-based experimental models. Examine if production offac tors known to mediate the communication between osteoblasts and osteoclasts (such as prostaglandins, inflammatory cytokines, hemopoietic growth factors, matrix molecules, and others)
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From page 93... ...
1995. Weight-bearing exercise and ground reaction forces: A 12-month randomized controlled trial of effects on bone mineral density in healthy postmenopausal women.
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From page 94... ...
1989. Osteopenia in the immobilized rat hind limb is associated with increased bone resorption and decreased bone formation.
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From page 95... ...
1996. Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: Cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress.
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From page 96... ...
1983. Arrested bone formation during spaceflight results in a hypomineralized skeletal defect.
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