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. Through her research, she will determine whether these will prevent bone loss experienced in space and serve as effective countermeasures.
Overview
Receptor Countermeasures to Bone Loss in Microgravity
Principal Investigator:
Carolyn L. Smith, Ph.D.
Organization:
Baylor College of Medicine
Technical Summary
The prevention of bone loss due to skeletal unloading is a complex problem whose reasons for this loss have not been fully elucidated. The overall goal of the NSBRI bone 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 may block the necessary remodeling that ensures adequate bone strength.
Studies to date suggest that good nutrition and exercise regimens will be insufficient to achieve this goal so pharmacological alternatives must be considered. The biological actions mediated by the estrogen receptor (ER) and vitamin D receptor (VDR) play key roles in the normal control of bone growth and skeletal turnover that are necessary for skeletal health. These receptors act by controlling the differentiation and/or function of osteoblasts and osteoclasts, and other cell types within the bone and bone marrow microenvironment, as well as play a role in calcium absorption (VDR). We hypothesize that the appropriate combination of an agent that will improve calcium absorption and encourage bone formation (VDR agonist) along with an agent that will reduce bone resorption (selective estrogen receptor modulators SERM) will achieve the goal of maintaining bone mass and bone strength.
To test this we have initiated studies to:
- Assess the ability of novel receptor agonists of the ER and VDR, alone or in combination, to modulate osteoblastogenesis, mature osteoblast function and osteoclastogenesis in vitro and in vivo, and
- Assess the ability of novel receptor agonists of the ER and VDR, alone or in combination, to prevent bone loss in the hindlimb suspension model of skeletal unloading.
The effects of unloading and of the countermeasures are being assessed by:
- Measuring changes in bone mineral density, histomorphometry, mechanical strength testing and biochemical markers of bone metabolism;
- Determining the effects of these treatments on osteoblastogenesis and osteoclastogenesis and function, and
- Characterizing gene expression profiles in bone resulting from skeletal unloading and administration of the countermeasures.
Our results to date indicate that ligands of both the ER and VDR possess the ability to attenuate bone loss in the rat hindlimb suspension model of skeletal unloading. Collectively, these studies will lead to a better understanding of the changes associated with skeletal unloading and will test the utility of VDR agonists and SERMS as countermeasures.
Earth Applications
Our findings have impacts on various aspects of research in the United States. First, we now have data to suggest that the responses to treatment with different ligands for the vitamin D receptor may be gender-dependent. While this has implications for astronauts, it is also useful information relative to health care for the general population, and we thus anticipate that this finding may stimulate research on the basis by which the sex-dependent response is achieved.
Our results on the EB1089 treatment of female rats suggests that it may be possible to achieve anabolic effects with a vitamin D receptor ligand, and if this finding is confirmed through subsequent analyses including histomorphometry, this may stimulate further research into the use of agents such as EB1089 for the treatment of post-menopausal osteoporosis. Finally, our results suggest that SERMs such as raloxifene may be an effective treatment for osteoporosis in human males, and this should stimulate further research into the use of this class of drugs in humans.
Our results on the EB1089 treatment of female rats suggests that it may be possible to achieve anabolic effects with a vitamin D receptor ligand, and if this finding is confirmed through subsequent analyses including histomorphometry, this may stimulate further research into the use of agents such as EB1089 for the treatment of post-menopausal osteoporosis. Finally, our results suggest that SERMs such as raloxifene may be an effective treatment for osteoporosis in human males, and this should stimulate further research into the use of this class of drugs in humans.
This project's funding ended in 2004