ABSTRACT
Based on our current understanding of ER-action, the interaction of the latent receptor with any ERligand induces a structural alteration in the receptor which promotes dissociation of the inhibitory heat-shock proteins (Beekman et al., 1993; McDonnell et al., 1995a). However, since the pure ERantagonists effectively activate ER, but promote bone loss, it indicates that this event alone is not sufficient for ER-mediated bone protective activities (Dukes et al., 1994; D.Morris and T.Willson, unpublished data). Following activation by estrogen, ER undergoes spontaneous dimerization permitting it to interact specifically and with high affinity to DNA response elements within target promoters. It may be at this stage that those ER-modulators which protect against bone loss, and those that do not, diverge. Specifically, it appears as if the pure antiestrogens, like ICI 182,780, interfere with the interaction of ER with DNA. The mechanism of this inhibitory activity is complex involving a combination of changes in nuclear-cytoplasmic shuttling, impaired dimerization and acceleration of the rate of ER turnover (Fawell et al., 1990; Dauvois et al., 1992). In contrast, all the other classes of ER-ligands, including GW5638 (I.Asplin and D.P.McDonnell, unpublished results) efficiently deliver ER to DNA and do not induce turnover of the receptor (McDonnell et al., 1995a). Upon reviewing the activity of the known ER ligands at each stage of the estrogen signaling pathway, it is apparent that the ability of a compound to activate ER and promote its association with DNA tracks well with bone protection (Table 2.1).
