Postmenopausal osteoporosis has become a major health and economic problem. This type of osteoporosis is characterized by a decrease in bone mass often resulting in fractures of the hip and spinal column. The etiology of osteoporosis remains to be clarified, but generally it is believed that bone remodeling (the balanced process of formation and resorption) has become """"""""uncoupled"""""""". Postmenopausal osteoporosis has been attributed to a decrease in circulating estrogens. It has been shown that therapeutic estrogen replacement prevents further loss of bone mass. However, the precise mechanism(s) of action for the effect of estrogen on bone has not been elucidated. Our hypothesis is that estrogens regulate the expression of an osteoblast (bone forming) specific gene network, and it is this group of gene products that interact to regulate osteoblast, and possibly, osteoclast activity.
The aim of our initial proposal was to determine if osteoblast-like cells contained estrogen receptors(ER). The presence of ER would support the hypothesis that estrogen exerts its effect directly on bone by regulating the transcription of key genes involved in bone remodeling. We proved that osteoblasts express estrogen receptors, and showed these cells respond to estrogen treatment as revealed by increased steady state mRNA levels coding for Type I collagen and transforming growth factor-beta (TGF-beta)--proteins known to be involved in bone formation. This present application aims to: 1) more completely characterize the influence of estrogens on Type I collagen gene transcription in relation to TGF-beta 2) characterize the role of the growth factors, TGF-beta and IGF-I, on estrogen receptor expression and 3) determine the role(s) of TGF-beta and IGF-I in modulating the effects of estrogen on osteoblast-like cells. Several questions pertaining to the seemingly close relationship between sex steroids and growth factors will be addressed. Does TGF-beta or IGF-I influence the osteoblastic response to estrogen? Are the effects of estrogens on the osteoblast transduced via autocrine or paracrine regulation by TGF- beta or IGF-I?The influence of estrogen on the osteoblast is pleiotropic and a few of the unambiguous responses have been identified. However, as the model for the regulation of osteoblast function by estrogen and other sex steroid hormones becomes more complete, so will our understanding of the role of the osteoblast in post-menopausal osteoporosis. These data may eventually lead to the development of alternative therapies for osteoporosis, and possibly a better means of preventing the disease.
| Liu, C; Wallace, K; Shi, C et al. (1996) Post-transcriptional stimulation of transforming growth factor beta 1 mRNA by TGF-beta 1 treatment of transformed human osteoblasts. J Bone Miner Res 11:211-17 |
