Faculty Bibliography

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.

Short-term exercise in growing rodents provided lifelong benefits to bone structure, strength, and fatigue resistance. Consequently, exercise when young may reduce the risk for fractures later in life, and the old exercise adage of "use it or lose it" may not be entirely applicable to the skeleton. INTRODUCTION: The growing skeleton is most responsive to exercise, but low-trauma fractures predominantly occur in adults. This disparity has raised the question of whether exercised-induced skeletal changes during growth persist into adulthood where they may have antifracture benefits. This study investigated whether brief exercise during growth results in lifelong changes in bone quantity, structure, quality, and mechanical properties. MATERIALS AND METHODS: Right forearms of 5-week-old Sprague-Dawley rats were exercised 3 days/week for 7 weeks using the forearm axial compression loading model. Left forearms were internal controls and not exercised. Bone quantity (mineral content and areal density) and structure (cortical area and minimum second moment of area [I(MIN)]) were assessed before and after exercise and during detraining (restriction to home cage activity). Ulnas were removed after 92 weeks of detraining (at 2 years of age) and assessed for bone quality (mineralization) and mechanical properties (ultimate force and fatigue life). RESULTS: Exercise induced consistent bone quantity and structural adaptation. The largest effect was on I(MIN), which was 25.4% (95% CI, 15.6-35.3%) greater in exercised ulnas compared with nonexercised ulnas. Bone quantity differences did not persist with detraining, whereas all of the absolute difference in bone structure between exercised and nonexercised ulnas was maintained. After detraining, exercised ulnas had 23.7% (95% CI, 13.0-34.3%) greater ultimate force, indicating enhanced bone strength. However, exercised ulnas also had lower postyield displacement (-26.4%; 95% CI, -43.6% to -9.1%), indicating increased brittleness. This resulted from greater mineralization (0.56%; 95% CI, 0.12-1.00%), but did not influence fatigue life, which was 10-fold greater in exercised ulnas. CONCLUSIONS: These data indicate that exercise when young can have lifelong benefits on bone structure and strength, and potentially, fracture risk. They suggest that the old exercise adage of "use it or lose it" may not be entirely applicable to the skeleton and that individuals undergoing skeletal growth should be encouraged to perform impact exercise.

Stress fractures are mechanically induced injuries resulting from fatigue damage to bone due to repetitive loading and are common injuries occurring in runners. In this study, we used computer simulations of marathon training programs to examine the effects of endurance running on femoral density, remodeling, and microdamage accumulation. Simulated remodeling activity increased in the femoral neck and proximal cortex and predicted microdamage increased in all regions examined after 16 weeks for each program. Daily running for three years produced more microdamage than the advanced training schedule over the same time period. Areas of high remodeling and damage corresponded to clinically observed locations of femoral stress fractures, indicating that the simulation may be useful in designing training programs to reduce fracture risk. (c) 2006 Elsevier Ltd. All rights reserved.

Mechanical loading of the skeleton is necessary to maintain bone structure and strength. Large amplitude strains associated with vigorous activity typically result in the greatest osteogenic response; however, data suggest that low-amplitude, broad-frequency vibration results in new bone formation and may enhance adaptation through a stochastic resonance (SR) phenomenon. That is, random noise may maximally enhance bone formation to a known osteogenic stimulus. The aims of this study were to (1) assess the ability of different vibration signals to enhance cortical bone formation during short- and long-term loading and (2) determine whether vibration could effect SR in bone. Two studies were completed wherein several osteogenic loading waveforms, with or without an additive low-amplitude, broad-frequency (0-50 Hz) vibration signal, were applied to the mouse ulna in axial compression. In study 1, mice were loaded short-term (30 s/day, 2 days) with either a carrier signal alone (1 or 2 N sine waveform), vibration signal alone [0.1 N or 0.3 N root mean square (RMS)] or combined carrier and vibration signal. In study 2, mice were loaded long-term (30 s/day, 3 days/week, 4 weeks) with a carrier signal alone (static or sine waveform), vibration signal alone (0.02 N, 0.04 N, 0.08 N or 0.25 N RMS) or combined carrier and vibration signal. Sequential calcein bone labels were administered at 2 and 4 days and at 4 and 29 days after the first day of loading in study 1 and 2, respectively; bone formation parameters and changes in geometry were measured. Combined application of the carrier and vibration signals in study 1 resulted in significantly greater bone formation than with either signal alone (P < 0.001); however, this increase was independently explained by increased strain levels associated with additive vibration. When load and strain levels were similar across loading groups in study 2, cortical bone formation and changes in geometry were not significantly altered by vibration. Vibration alone did not result in any new bone formation. Our data suggest that low-amplitude, broad-frequency vibration superimposed onto an osteogenic waveform or vibration alone does not enhance cortical bone adaptation at the frequencies, amplitudes and loading periods tested.

Women are at greater risk of tearing their knee anterior cruciate ligament (ACL) than men participating in similar athletic activities. There is currently no conclusive explanation for this disparity; however, as ACL injuries in women have been linked with estrogen fluctuations during the menstrual cycle, one hypothesis is that estrogen has a direct detrimental effect on knee ligament mechanical properties. This study investigated the influence of estrogen and its receptors (ER alpha and ER beta) on knee ligament mechanical properties. This was achieved by testing the viscoelastic and tensile mechanical properties of knee medial collateral ligaments (MCL) and ACLs from: 1) male Sprague-Dawley rats treated with either estrogen (17alpha-ethynylestradiol; 0.03 mg/kg) or an ER alpha-specific agonist (propyl pyrazole triol; 2 mg/kg), and 2) female mice with a null mutation of the gene encoding for ER beta. Estrogen treatment had no significant effects on the viscoelastic or tensile mechanical properties of the rat MCL or ACL. Similarly, pharmacological stimulation of ER alpha using a selective agonist in rats and genetic modulation of ER beta by null mutation of its gene in mice did not influence MCL or ACL properties. These data indicate that estrogen does not have a major direct effect on ligament mechanical properties. Energies for the prevention of the disproportionately high rate of knee ligament injuries in women may be better spent focusing on more established and modifiable risk factors, such as abnormalities in neuromuscular control about the knee.

Bone is a dynamic tissue that is constantly renewed. The cell populations that participate in this process--the osteoblasts and osteoclasts--are derived from different progenitor pools that are under distinct molecular control mechanisms. Together, these cells form temporary anatomical structures, called basic multicellular units, that execute bone remodeling. A number of stimuli affect bone turnover, including hormones, cytokines, and mechanical stimuli. All of these factors affect the amount and quality of the tissue produced. Mechanical loading is a particularly potent stimulus for bone cells, which improves bone strength and inhibits bone loss with age. Like other materials, bone accumulates damage from loading, but, unlike engineering materials, bone is capable of self-repair. The molecular mechanisms by which bone adapts to loading and repairs damage are starting to become clear. Many of these processes have implications for bone health, disease, and the feasibility of living in weightless environments (e.g., spaceflight).