Endocrine regulation of skeletal metabolism

Abstract

Estrogen is essential for skeletal growth and the maintenance of adult bone mass. This fact is clearly illustrated by the occurrence of osteoporosis in postmenopausal women. Although the bone sparing effects of estrogen have been recognised for a very long time, little is still known about its mechanism of action in the skeleton. Skeletal effects of estrogen may be indirect via the modulation of other hormones, as well as direct, via estrogen receptors in skeletal cells. Two estrogen receptors have been cloned and these have been denoted ERa and ERb. In part of this thesis the expression and distribution of the novel estrogen receptor-beta (ERb) has been investigated. It has been demonstrated that ERb is expressed in the hypertrophic zone in the growth plate and in osteoblasts, suggesting a functional role for this receptor, as a mediator of estrogenic effects in the skeleton. The biological function of estrogen receptors has also been investigated in mice lacking ERa, ERb or both receptors. It has been demonstrated that ERa as well as ERb is of importance in the female mouse skeleton, whereas only ERa is of importance in the male skeleton.The expression and regulation by hormones and cytokines of the recently cloned bone sparing factor osteoprotegerin (OPG) has also been investigated. It has been demonstrated that glucocorticoids decrease OPG mRNA levels in primary human osteoblast-like cells, a finding, which provides a possible mechanism whereby high levels of glucocorticoids, may increase bone resorption. It has also been demonstrated that IL-1a, a pro-inflammatory cytokine, increases OPG mRNA levels in cultured human osteoblasts.Finally the transcription factor C/EBPa was found to be co-expressed with the growth hormone receptor in the stem cell layer of the rat growth plate, indicating that C/EBPa might be involved in the regulation of longitudinal bone growth.This thesis contributes to our understanding of how estrogen exerts its effects on the skeleton in males and females. It has also increased our basic knowledge concerning the effects of hormones and growth factors on OPG gene expression in osteoblasts. This knowledge may be valuable for the development of new treatment strategies for children with growth disturbances and adults with metabolic bone diseases.