Receptor Countermeasures to Bone Loss in Microgravity
Carolyn L. Smith, Ph.D.
Baylor College of Medicine
Studies have shown that nutrition and exercise are not enough to maintain bone strength in space. Dr. Carolyn Smith is studying the effects of pharmaceutical agents on two mechanisms the body uses to regulate bone growth and density: the estrogen receptor and the vitamin D receptor. Her research seeks to define the appropriate combination of agents that will prevent loss of bone and maintain bone strength.
NASA Taskbook Entry
The prevention of bone loss due to skeletal unloading is a complex problem and the reasons for this loss have not been elucidated. The overall goal of the NSBRI Bone Loss Team is to develop countermeasures that will not only prevent quantitative loss of bone, but also maintain bone strength. Measures that simply prevent resorption may maintain mass but block the necessary remodeling to ensure appropriate bone strength. Biological actions mediated by the ER and VDR play key roles in the normal control of bone growth and turnover that is necessary for skeletal health. These receptors act by controlling: 1). the differentiation of the precursors of OBs and OCs; 2). the functions, including gene expression, of mature OBs and OCs, and/or; 3). other cell types within the bone and bone marrow microenvironment that control 1 and 2 (e.g., stromal cells and monocytes). In addition, they play important roles in regulating the expression of systemic factors that contribute to the overall balance of bone remodeling in the skeleton. Finally, VDR is critical for efficient intestinal calcium absorption. We hypothesize that the appropriate combination of an agent that will improve calcium absorption (VDR agonist) and an agent that will reduce bone resorption (a bone-selective estrogen receptor agonist, STEAR) will achieve these goals. Indeed, there may be synergistic interactions between these receptors that enhance the actions over any one agent used alone.
This research outlines studies designed to investigate the physiological, cellular and molecular alterations that occur in the hindlimb suspension (HLS) rat model of skeletal unloading and to evaluate the ability of ER and VDR agonists to counteract the deleterious effects of mechanical unloading on the mature rat, with respect to parameters associated with the skeleton and its associated soft tissues, endocrine system and calcium homeostasis. In so doing, we will obtain molecular, cellular and tissue data that will provide information on the ability of our countermeasures to prevent unloading-induced bone loss, as well as information on the mechanisms that contribute to this undesired consequence of microgravity.
With our two specific aims, we are examining the role of these agonists in both male and female animals. This is important since astronaut crews are composed of both genders and previous unloading studies have revealed gender differences in unloading-induced bone loss. This will lead to a better understanding of the causes of skeletal unloading and the means to prevent bone loss. In addition, the results of these studies will provide a foundation for future experiments that will examine the ability of the most promising pharmacological countermeasure(s) to maintain bone mineral density and strength in established models of unloading-induced osteopenia in humans and/or during space flight.
The applications of this research to Earth-based populations are most relevant to populations for whom osteoporosis is a concern. For instance, individuals at risk for developing postmenopausal osteoporosis would benefit from the development of protocols able to prevent or treat this condition that is associated with a significant morbidity and high economic cost (approximately 17 billion according for the National Osteoporosis Foundation) for the 10 million Americans estimated to have this disease. It is clear that estradiol is no longer a viable option for prevention of osteoporosis for most women and raloxifene is not well-tolerated by a significant number of women. The ability to use EB1089 represents an opportunity to employ a drug that affects the activity of a relatively unexplored pharmacological target relative to osteoporosis, the vitamin D receptor. The ability of EB1089 to exert a greater effect in females than males suggests that this agent may be particularly effective in the treatment or prevention of postmenopausal osteoporosis. Moreover, it should be noted that administration of vitamin D receptor ligands is currently being evaluated for treatment and/or prevention of various types of cancer such as breast and prostate, and use of EB1089 for osteoporosis has the potential to impact the incidence and outcome of diseases that affect hundreds of thousands of Americans each year. Finally, although it is not the intent of this project nor the mission of NSBRI to determine the molecular mechanisms by which gender-specific actions of EB1089 are achieved, the data produced in this application has provided important preliminary data that we are pursuing though other venues.
Ultimately, this may provide information on the differences between males and females that can be exploited to develop compounds for the prevention of disuse-induced osteoporosis with optimal efficacy for males and females.