Graduate Thesis Or Dissertation
 

The Role of Bone Marrow Adipose Tissue in Bone Loss During Spaceflight and Simulated Spaceflight in Rodents

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  • The reduction in mechanical load imparted on the body during spaceflight presents unique physiological challenges. One detrimental and seemingly unavoidable response to microgravity is rapid bone loss. This adaptation is hazardous not only to astronaut health, but to the success of long-duration exploration-class missions. Skeletal adaptation to spaceflight in astronauts typically includes rapid site-specific bone loss from unbalanced bone turnover, primarily in the femur, hip and vertebra. Studies of rats in space and biochemical markers from astronauts typically indicate unbalanced bone turnover results from an increase in bone resorption and either no change or a decrease in bone formation. An increase in bone marrow adipose tissue (MAT) is concurrently observed with bone loss in ground-based conditions of disuse or reduced mobility, such as bed rest. While the precise role of bone marrow adiposity is unclear, it has concurrently been associated with a decrease in bone formation. The invasive nature of bone marrow analysis and high cost associated with long-term disuse studies makes human-based research difficult to accomplish. The use of rodent subjects is a valuable tool in research for desirable size, cost, lifespan and comparable physiological systems to humans, and was thus used in the studies described in this dissertation. The central hypothesis of this dissertation states skeletal disuse results in bone loss, in part, from a reduction in ability to form osteoblasts, and occurs concurrently with MAT infiltration. Furthermore, we hypothesize that increased MAT plays a causative role in bone loss. If this hypothesis is correct: 1) an inability to produce MAT is protective against disuse-induced bone loss, and 2) an ability to produce high quantities of MAT exacerbates disuse-induced bone loss. The role of bone marrow adiposity in disuse-induced bone loss was evaluated using archived bone specimens from rats flown in space for 14 days and using mice subjected to hindlimb-unloading (HU), a ground-based model for spaceflight. The effects of the 14-day spaceflight on bone mass, density and microarchitecture in weight bearing (femur and humerus) and non-weight bearing (2nd lumbar vertebra and calvarium) bones in female rats insufficient in ovarian hormones due to ovariectomy are presented in Chapter 2. In the context of established ovarian hormone deficiency, a 14-day spaceflight resulted in bone- and bone compartment-specific decrements in bone acquisition and a negative turnover balance leading to deficits in bone mass and defective microarchitecture beyond that induced by ovx. The observed changes demonstrate the importance of evaluating multiple bones and bone compartments. The effects of a 14-day spaceflight on bone mass, bone resorption, bone formation, and MAT in lumbar vertebrae of the ovx rats was subsequently evaluated and the results are described in Chapter 3. The increase in MAT observed during this short-duration spaceflight did not impair osteoblast activity, reduce the interval osteoblasts are present on bone surfaces or decrease generation of new osteoblasts. These findings argue against the hypothesis that increased MAT produces factors that suppress bone formation. Although increased MAT did not impact osteoblast kinetics or bone formation, it is important to note that bone formation did not increase during spaceflight to compensate for the increase in bone resorption. This finding is consistent with the hypothesis that, in the context of ovarian hormone deficiency, osteoblast precursors are diverted to adipocytes instead of osteoblasts during spaceflight. These studies were the first large-scale investigation into the influence of microgravity on multi-site microarchitecture and MAT in slowly growing rats. The findings also indicated the importance of location in evaluation. A 14-day spaceflight did not result in loss of cortical bone in femur, humerus or calvaria. Cancellous bone loss was observed in femur and vertebra but not in humerus. The lumbar vertebra is not a primary weight-bearing site in rodents, yet it exhibited bone loss from increased bone resorption and no change in bone formation, as well as an increase in MAT. Importantly, our findings suggest that while MAT may increase during spaceflight it does not impair ongoing bone formation. MAT-deficient Kit[superscript W/W-v] (MAT-) mice were used to determine if absence of MAT reduced bone loss in HU mice after 14 days. The results from this study are described in Chapter 4. MAT- mice had a greater reduction in bone volume fraction than WT mice. While both HU groups had greater osteoclast perimeter than controls, HU MAT- mice had greater osteoblast perimeter, mineral apposition rate and bone formation rate compared to other treatment groups. The increase in bone formation was not sufficient to balance the increase in bone resorption during disuse, ultimately resulting in reduced bone that was of a greater magnitude in MAT-deficient mice. Targeted gene profiling further suggested a differential response of WT and MAT- mice to HU. To verify that the differences were not due to kit deficiency, we reconstituted the hematopoietic system in the Kit[superscript W/W-v] mice with WT hematopoietic stem cells. Adoptive transfer of WT bone marrow-derived hematopoietic stem cells reconstituted c-kit but not MAT in KitKit[superscript W/W-v] mice. The WT→ Kit[superscript W/W-v] mice lost cancellous bone following 14 days of HU. Together, the results do not support the hypothesis that MAT potentiates disuse-induced bone loss in mice. MAT was not increased in WT mice following HU and MAT deficiency was not protective against disuse-induced cancellous bone loss. Results from this study indicate MAT may actually have a protective role in limiting disuse-induced osteopenia, perhaps by limiting the magnitude of increased bone turnover. Chapter 5 describes results using mice with high MAT due to leptin deficiency (ob/ob) to determine if excess MAT exacerbated bone loss in HU mice after 14 days. ob/ob mice were pair-fed to WT mice to prevent the development of morbid obesity, but still maintained a greater body weight and abdominal adipose tissue than the WT mice. ob/ob mice had lower femoral bone mineral content and length, but no difference in cancellous bone volume fraction in the metaphysis and epiphysis. HU resulted in cancellous bone loss in metaphysis and epiphysis. While osteoblast perimeter was increased after HU, it was not sufficient to compensate for the increase in bone resorption leading to a reduction in cancellous bone. No significant interactions between genotype and treatment were detected for any of the endpoints measured. Together, the results do not support the hypothesis that high levels of MAT exacerbate disuse-induced bone loss in mice. The findings from this study indicate that having higher levels of MAT did not influence the bone response to disuse. While the central hypothesis that inadequate formation of osteoblasts contributes to bone loss and occurs concurrently with increased MAT infiltration was partially accepted in spaceflight, it was rejected in hindlimb unloading. Although we did observe an increase in MAT following spaceflight, it was not associated with altered osteoblast turnover or decreased bone formation. During HU, MAT levels did not change but bone formation increased. Importantly, bone resorption was increased during spaceflight and HU. Therefore, bone loss resulted from inadequate coupling of bone formation to compensate for the increase in bone resorption. These studies suggest that a simple relationship between MAT and bone mass does not exist and that targeting MAT to increase bone mass may not be an effective strategy.
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