Estrogen receptors α and ß have different gender-dependent effects on the adaptive responses to load bearing in cancellous and cortical bone.

To determine the effect of estrogen receptors (ER) α and ß on bones' adaptive response to loading, we subjected the right tibiae of mice lacking ERα or ERß activity to either axial loading or to disuse. Adaptive changes in architecture were assessed by comparing differences between the right (treated) and left (control) tibiae in these genotypes as assessed by microcomputed tomography. In female ERα(-/-) mice, the net-osteogenic response to loading was lower in cortical bone compared with their wild-type littermates (11.2 vs. 20.9% in ERα(+/+)), but it was higher in both cortical and cancellous bone of male ERα(-/-) mice (cortical 20.0 vs. 4.6% in ERα(+/+); cancellous 30.0 vs. 5.3% in ERα(+/+), P < 0.05). In ERß(-/-) male and female mice, the net-osteogenic response to loading was higher in cortical bone (males 10.9 vs. 3.9% in ERß(+/+); females 18.5 vs. 15.8% in ERß(+/+), P < 0.05) but no different from controls in cancellous bone. The bone loss in response to disuse was less in cancellous bone of ERα(-/-) mice than in controls (-15.9 vs. -21.3%, respectively, P < 0.05) but no different at any other site or between any other groups. Our conclusion is that functional ERα enhances the net-osteogenic response to loading in cortical but not cancellous bone in female mice but reduces it in males. ERß decreases the response to loading in cortical bone of males and females but has no effect in cancellous bone. Bone loss due to disuse in cortical bone is unaffected by ER status, but in cancellous bone, functional ERα contributes to greater disuse-related bone loss.

The skeletal responsiveness to mechanical loading is enhanced in mice with a null mutation in estrogen receptor-beta.

Mechanical loading caused by physical activity can stimulate bone formation and strengthen the skeleton. Estrogen receptors (ERs) play some role in the signaling cascade that is initiated in bone cells after a mechanical load is applied. We hypothesized that one of the ERs, ER-beta, influences the responsiveness of bone to mechanical loads. To test our hypothesis, 16-wk-old male and female mice with null mutations in ER-beta (ER-beta(-/-)) had their right forelimbs subjected to short daily loading bouts. The loading technique used has been shown to increase bone formation in the ulna. Each loading bout consisted of 60 compressive loads within 30 s applied daily for 3 consecutive days. Bone formation was measured by first giving standard fluorochrome bone labels 1 and 6 days after loading and using quantitative histomorphometry to assess bone sections from the midshaft of the ulna. The left nonloaded ulna served as an internal control for the effects of loading. Mechanical loading increased bone formation rate at the periosteal bone surface of the mid-ulna in both ER-beta(-/-) and wild-type (WT) mice. The ulnar responsiveness to loading was similar in male ER-beta(-/-) vs. WT mice, but for female mice bone formation was stimulated more effectively in ER-beta(-/-) mice (P < 0.001). We conclude that estrogen signaling through ER-beta suppresses the mechanical loading response on the periosteal surface of long bones.

Estrogen receptor beta: the antimechanostat?

We have known for sometime that sex hormones influence the growth, preservation, and loss of bone tissue in the skeleton. However, we are only beginning to recognize how estrogen influences the responsiveness of the skeleton to exercise. Frost's mechanostat theory proposes that estrogen reduces the mechanical strain required to initiate an osteogenic response, but this may only occur at the endocortical and trabecular bone surfaces. The discovery of estrogen receptors alpha and beta may help us to understand the bone surface-specific effects of exercise. Findings from estrogen receptor knockout mice suggest that the activity of ERalpha may explain the positive interaction between estrogen and exercise on bone formation near marrow, that is, endocortical and trabecular bone surfaces. Estrogen inhibits the anabolic exercise response at the periosteal surface, and this we propose is due to the activation of ERbeta. Signaling through this receptor retards periosteal bone formation and suppresses gains in bone size and bone strength, and for these reasons it behaves as an antimechanostat.

Mechanosensitivity of the rat skeleton decreases after a long period of loading, but is improved with time off.

After the initial adaptation to large mechanical loads, it appears as though the skeleton's responsiveness to exercise begins to wane. To counteract the waning effects of long-term mechanical loading, "time off" may be needed to improve the responsiveness of bone cells to future mechanical signals and reinitiate bone formation. The aim of this study was to determine whether bone becomes less sensitive to long-term mechanical loading and whether time off is needed to improve mechanosensitivity. Fifty-seven female Sprague-Dawley rats (7-8 months of age) were randomized to one of following groups: Group 1 loading was applied for 5 weeks followed by 10 weeks of time off (1 x 5); Group 2 loading was applied for 5 weeks, followed by time off for 5 weeks and loading again for 5 weeks (2 x 5); Group 3 loading was applied continuously for 15 weeks (3 x 5); Group 4 age-matched control group; and Group 5 baseline control group. An axial load was applied to the right ulna for 360 cycles/day, at 2 Hz, 3 days/week at 15 N. At the end of the intervention, all three loaded groups showed similar increases in bone mass, cortical area, and I(MIN) in response to mechanical loading(.) Bone formation rate of the loaded ulna was increased in the first 5 weeks of loading for all three loaded groups; however, during the last 5 weeks, it was only significantly increased in the group that had time off (2 x 5) (P < 0.05). The group that had time off (2 x 5) also showed greater improvements in work to failure compared to the group loaded for 5 weeks (1 x 5) and the entire 15 weeks (3 x 5). A second experiment showed that the waning effect of long-term loading on the skeleton is not a result of aging. In conclusion, mechanical loading of the rat ulna results in large improvements in bone formation during the first 5 weeks of loading, but continual loading decreases the osteogenic response. Having time off increases bone formation and improves the resistance to fracture.