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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online June 21, 2002 as doi:10.1096/fj.01-0913fje. |
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Department of Biomedical Engineering, State University of New York at Stony Brook, Stony Brook, New York, USA; and
* The Jackson Laboratory, Bar Harbor, Maine, USA
2Correspondence: Department of Biomedical Engineering, Psychology A Building, 3rd Floor, State University of New York at Stony Brook, Stony Brook, NY, 11794-2580, USA. E-mail: stefan.judex{at}sunysb.edu
SPECIFIC AIMS
Subtle genotypic variations may have an powerful impact on achieving and retaining trabecular bone quantity and quality, but it is not clear if the genome also influences how an individual may respond to anabolic and catabolic interventions. With clear evidence that the skeleton will rapidly adapt to both anabolic and catabolic mechanical factors, we hypothesized that genetic variability resulting in differences in bone mass and morphology associated with distinct strains of mice would also lead to a differential adaptive response to altered levels of mechanical demand.
PRINCIPAL FINDINGS
1. Genetic variations are associated with a differential response to anabolic stimuli
Genetic heterogeneity in humans, even within a given race, is reflected in substantial differences in body size and shape, peak bone mass, and rates of fracture due to osteoporosis; consequently it is difficult to separate environmental from genetic effects on treatment outcomes. Inbred mouse strains with distinct bone phenotypes provide an effective system to establish the degree to which anabolic or catabolic stimuli can modulate bone mass and morphology. Previous investigations have demonstrated that several of these inbred mouse strains, despite similar levels of body mass, exhibit greatly different levels of bone mineral density, with the femur ranging from a relatively low BMD of 0.45 mg/ mm3 in C57BL/6J (B6) mice to BALB/cByJ (BALB) mice, which are 20% higher (0.55 mg/ mm3), and finally to the high BMD C3H/HeJ (C3H) mice, which are > 50% higher (0.69 mg/ mm3) than the B6 mice. Like humans, the mouse data support a clear influence of the genome on bone mass. But like the human, it is unclear whether these subtle variations influence the sensitivity of the bone to catabolic pressures toward osteoporosis or the potential of anabolic therapies to curb this bone loss.
In contrast to most currently FDA-approved interventions, mechanical signals, such as those which arise with exercise, are capable not only of suppressing osteoclast formation, but can also stimulate osteoblastic activity. For our first specific aim, adult female C57BL/6J (B6), BALB/cByJ (BALB), and C3H/HeJ (C3H) mice were subjected to extremely low-level (0.25 g-Earth’s gravitational field), high-frequency (45 Hz) mechanical stimuli via a vibrating plate for 10 min/day. In trabecular bone of the proximal tibia, bone formation rates with tissue volume as referent (BFR/TV) of mechanically stimulated low bone mineral density (BMD) B6 mice were 69% greater (P<0.04) than BFR/TV of intra-strain control mice. Despite the brief length of the intervention, higher trabecular bone formation rates coincided with a 85% (P<0.01) larger bone volume (BV/TV) and 50% larger trabecular thickness (P<0.009) in vibrated mice (Fig. 1
). When bone formation rates were calculated with BS as referent, the greater bone volume fraction (and bone surface) negated the larger BFR/TV, resulting in no significant differences in BFR/BS between mechanically stimulated and control B6 mice. In BALB mice, mechanical stimulation increased BFR/BS by 32% (P<0.04) but bone structural indices, including BV/TV, were unaffected (Fig. 1
and Fig. 2
). The increase in bone formation rates was primarily achieved by an increase in double-labeled surfaces (dLS/BS) (+56%, P<0.01) rather than by increased MAR. In contrast to the responsiveness of the skeleton of B6 and BALB mice, no significant effects of mechanical stimulation were observed in high bone density C3H/HeJ mice. Across the three strains of mice, bone density was inversely related to mechanosensitivity whereas bone turnover was positively associated with enhanced bone formation by low-level mechanical signals.
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2. Genetic variations are associated with a differential response to catabolic stimuli
The skeleton will also adapt to the removal of its mechanical environment such as occurs in space flight, bedrest, and/or cast immobilization, and the increase in bone resorption together with a decrease in bone formation will ultimately result in osteoporosis. When the mechanical loading environment was removed from the tibia of the three strains of mice via hind limb suspension, disuse failed to affect histomorphometric indices in the proximal tibia of low density B6 mice. In the medium density BALB mice, disuse suppressed BFR/BS by 55% (P<0.02), dLS/BS by 46% (P<0.04), and mineral apposition rates by 45% (P<0.001), contributing to a 43% (P<0.007) reduction in trabecular bone volume compared to control BALBs (Figs. 1
, 2)
. Similar to mechanical stimulation, mechanical disuse did not elicit a tissue level response in tibial trabecular bone of high bone density C3H mice.
CONCLUSIONS
These data indicate a strong influence of genetic variability on the plasticity of trabecular bone to anabolic and catabolic mechanical stimuli (Fig. 3)
. The extremely low-level mechanical stimuli superimposed on normal daily activities for 10 min/day were highly anabolic in the proximal tibia of B6 and BALB mice, whereas no significant effect of this specific stimulus was detected in the high bone density C3H mice. Disuse suppressed bone formation rates and bone volume in BALB mice but failed to significantly influence bone’s formative response in the other two strains, one of lower bone density, the other higher. Extrapolating these results to the human skeleton may provide insight into the inconsistent efficacy of treatment regimens and into the individual variation in the pathogenesis of disuse osteoporosis. The results of this study also suggest that some people who benefit from a genetically predetermined higher bone mass, as well as slower rates of bone turnover (and thus slower rates of bone loss), may have a differential sensitivity to increases or decreases in exogenous stimuli, thus reducing the effect of age, disuse, or menopause-induced uncoupling of bone formation and resorption. African American women who have a higher bone mineral density have a slower rate of postmenopausal bone loss than Caucasian women, attributes that combine to result in osteoporotic fracture rates one-half that of Caucasian women. It has been proposed that the higher levels of bone mineral density in young adult African Americans is a result not only of a genetically predetermined higher baseline, but an adaptive response to increased force magnitudes associated with a larger body mass. Subsequent comparisons of spinal bone mineral density between Caucasian and African American women, however, suggest that the difference in BMD cannot be explained by body mass; African American women had a higher bone mineral density even at the same body mass. In light of our data, the skeleton of Caucasian women is perhaps more prone to osteoporosis but may also be more sensitive to interventions aiming at prohibiting further bone loss.
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In summary, our data indicate a genetic basis for the sensitivity of trabecular bone to exogenous mechanical stimuli whether anabolic or catabolic in nature. Going one step further, it is reasonable to conclude that genetic variability will influence other systems (e.g., neural, cardiovascular, immune) to be differentially responsive to biochemical or biophysical perturbations. Genetic and molecular studies that identify specific genes responsible for the differential regulation of bone’s sensitivity to exogenous stimuli would facilitate the development of novel diagnostics to identify those at greatest risk of disease and thus allow therapies to focus on those individuals. Further, therapeutics that take advantage of the responsiveness of the skeleton to exogenous stimuli to effectively protect bone quality and quantity could be designed based on genetic predispositions.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0913fje; to cite this article, use FASEB J. (June 21, 2002) 10.1096/fj.01-0913fje 
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