Considerable evidence indicates that early osteoblast progenitors are an important target of estrogen; and that the increased bone remodeling, and bone loss, caused by estrogen deficiency is due to an increase in osteogenic stem cell replication which causes not only an increase in bone formation but also an increase in osteoclastogenesis and bone resorption. However, the latter is excessive and bone loss ensues. The purpose of the proposed studies is to determine the effect of 17beta-estradiol on the replication of osteogenic stem cells obtained from the murine bone marrow. To do this, stem cell replication will be measured using a replating assay, and the osteoblast progeny will be identified by in situ hybridization to detect osf-2 (an osteoblast specific transcription factor) and osteocalcin, made by differentiated osteoblasts. Neutralizing antibodies or growth factor antagonists will be used to determine whether the effects of 17beta-estradiol on osteogenic stem cell replication are mediated by endogenously produced growth factors and cytokines such as transforming growth factor-beta, IL-6 type cytokines, or bone morphogenetic proteins. In the course of conducting this work, the applicant will gain expertise in the analysis of bone cell function using state of the art techniques that are already established or currently under development in our institution. More importantly for her future career, the results of the work proposed here will make a significant contribution to the understanding of the pathophysiology of osteopenia caused by estrogen deficiency, and thus will put her in a strong position to compete for her own funding as an independent investigator.
| Di Gregorio, G B; Yamamoto, M; Ali, A A et al. (2001) Attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the murine bone marrow by 17 beta-estradiol. J Clin Invest 107:803-12 |
