All ETDs from UAB

Advisory Committee Chair

Jay M McDonald

Advisory Committee Members

Joanne Murphy-Ullrich

Selvarangan Ponnazhagan

Xu Feng

Chenbei Chang

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Rapid bone loss occurs during prolonged periods of weightlessness experienced by astronauts during spaceflights which leads to osteopenia and increased fracture risk upon return to earth. Spaceflight studies have shown that the bone loss occurs as a result of both a decrease in bone formation and an increase in bone resorption, however, the molecular mechanisms still need to be elucidated. Previous studies from our laboratory and other groups have indicated that modeled microgravity leads to inhibition of osteoblastogenesis and a stimulation of adipogenesis of human mesenchymal stem cells in osteogenic medium which is most likely mediated by a decrease in RhoA expression, disruption of stress fibers, and involvement of integrin signaling. In this study, we have established an in vitro system to study the molecular mechanisms of osteoclastogenesis in modeled microgravity and determined that there is a partial activation of osteoclastogenesis signaling including the activation of a key osteoclastogenesis transcription factor, NFATc1, due to modeled micgrogravity exposure of 24h. In order to study the effect of microgravity on the bone in vivo, we have used the hindlimb unloading mouse model system that is also used to study disuse osteoporosis. We observed that hindlimb unloading for 2 wks and 4wks leads to rapid a significant reduction in the bone mineral density, loss of 3-D microstructure, and bone strength. We used the hindlimb unloading system to test for effective countermeasures to prevent both microgravity and disuse-induced bone loss. Since bone loss in microgravity and disuse osteoporosis is a result of both decrease in bone formation and an increase in bone resorption, we used two drugs; a bisphosphonate, alendronate that is antiresorptive, and parathyroid hormone (PTH) that stimulates bone formation. Interestingly, the effect of alendronte and PTH together on the long bones of hindlimb unloaded mice was neither additive nor synergistic and alendronate alone was able to prevent loss at both the trabecular and cortical region. Thus, we have established an in vitro modeled microgravity system to study the underlying molecular mechanisms of osteoclastogenesis and, also used an in vivo mouse hindlimb unloading system to test for countermeasures and the results of this dissertation suggest that long term spaceflights and patients with disuse osteoporosis are likely to respond optimally to bisphosphonates therapy alone rather than combination therapy with bisohosphonates and PTH.

Share

COinS