Bone loss is an increasing problem that affects all demographics. This loss occurs when a load bearing bone is not used for a prolonged periods of time. Such an example of disuse would be an astronaut on a mission or a sick person undergoing bed rest. Currently, methods are being developed to help prevent this loss as it poses a serious problem to long duration space missions or critically ill patients. Ways of recovering bone mass such as running or lifting weights will not work for these people due to a zero -g environment or they would be already too weak to do such activities. The experimental methods focus on various speeds and magnitudes of vibrations which can induce strain even in a zero-g environment or on a weakened patient. Some of these methods have been rather successful in increasing overall bone mass but the amount it affects bones sections relative to each other is largely unexamined. To induce disuse in mice a hind limb suspension apparatus is utilized. This lift’s the mice’s tail upsing no pressure to be exerted on the rear limbs. The mice still maintain mobility via their front limbs. To examine the effects a VivaCT scanner is employed. This generates images of the bone cross-sections while not harming the mouse. These images can later be reconstructed into a 3D model.

Results:

+ During the 1-3 week period bone volume decreased an average of 1%.
+ During the 3-6 week period bone volume increased an average of 4%
+ During weeks 1-3 the muscle volume decreased and average of 10%
+ During Weeks 4-6 muscle mass volume increased 7%

The bone seemed to be more responsive to mechanical loading (walking) than unloading (immobilized).
The reverse of this is true for the muscle.

The distribution of loss/gain rather than being grouped around one value suggests that there is a controlling factor that was spread through the genetically heterogeneous population.

My research focuses on how organ systems, such as the skeleton, respond to altered functional demand. Specifically, my lab has been interested in combining genetic, molecular, and biomechanical approaches to elucidate how bone regulates its quantity and quality and how mechanical stimuli may perturb this regulation. An improved understanding of how external signals are translated into a biological response require the rigorous integration of engineering with biology, from the genome to the molecular, cellular, and tissue level. This understanding will, ultimately, lead to the design of pharmacological and non-pharmacological (e.g., mechanical or nutritional) interventions that will enhance tissue strength in young adults and prevent the loss of tissue quantity and quality during osteoporosis, aging, or space flight.  To this end, genetic (e.g., QTL) and molecular (e.g., RT-PCR, immunocytochemistry, or microarrays) assays are used to relate specific loci on chromosomes and the expression level of corresponding genes to traits at the level of the tissue.  These traits are rigorously defined by their chemical, morphological, and mechanical properties by cutting edge technology such as MRI, high resolution computed tomographic imaging, in situ infrared spectroscopy, or finite element modeling.

The National Research Council's Space Studies Board has stated that a principal physiologic hurdle to man's extended presence in space is the osteopenia and sarcopenia which parallels reduced gravity. The extent of the loss is extremely high, approaching a decrease in bone mineral density (BMD) in the lower appendicular skeleton at a rate of 1.6% per month and reducing maximal voluntary contractions of some muscle groups at a rate of 5% per month. Interestingly, the amount of bone (and muscle) loss between individual astronauts is highly variable with some astronauts losing large amounts of tissue while others are largely unaffected. This large individual variability, which has also been observed during bedrest and immobilization studies on Earth, may be accounted for, at least to a large extent, by genetic variations which may give rise to a differential mechanosensitivity of the musculoskeleton. We have collected preliminary data demonstrating that genetically distinct inbred strains of mice also demonstrate a distinct sensitivity to conditions of simulated weightlessness; while as much as 60% of trabecular bone is lost in the hindlimbs of BALB/cByJ mice within 3 weeks of disuse, the same conditions leave trabecular bone quantity and quality nearly unchanged in C3H/HeJ mice. In this proposal, we aim to elucidate this genetic basis of the sensitivity of the musculo-skeleton to the loss of appropriate mechanical signals by identifying the quantitative trait loci (QTL) responsible for the difference exhibited between these two strains of inbred mice. The identification of QTL (and ultimately the responsible genes) may be used as both a critical diagnostic sensor for the identification of astronauts that are in greatest need of pharmacologic and/or biomechanical countermeasures in space and as a discovery tool of novel drug targets against the loss of musculo-skeletal tissue.