The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis

Abstract

Estrogen therapy and hormone therapy are effective options for the prevention and treatment of osteoporosis, although because of their significant side effect profile, long term use for these applications is not recommended. Whereas SERMs (Selective Estrogen Receptor Modulators) exhibit a more favorable side effect profile, the currently available medicines in this class are substantially less effective in bone than classical estrogens. However, the results of substantial efforts that have gone into defining the mechanisms that underlie the pharmacology of estrogens, antiestrogens and SERMs have informed the development of the next generation of SERMs and have led to the development of TSECs (Tissue Selective Estrogen Complexes), a new class of ER-modulator. Further, the recent determination that the oxysterol 27-hydroxycholesterol functions as an endogenous SERM has highlighted an unexpected link between hypercholesterolemia and bone biology and must be considered in any discussions of ER-pharmacology. This review considers the most recent progress in our understanding of ER pharmacology and how this has and will be translated into new medicines for the treatment and prevention of osteoporosis.

Figure 1. Mechanisms of estrogen receptor (ER) action

Upon binding an agonist the ERs (ERα and ERβ) can form homo or heterodimers and translocate to the nucleus where they associate with coactivator proteins (CoA) and impact transcription by either binding DNA directly at estrogen response elements (EREs), or by tethering to DNA-bound transcription factors such as AP1, nuclear factor-κB and Sp1. Alternatively ERs can act in a non-genomic manner by interacting with c-Src protein kinase complex, the regulatory subunit of phosphoinositide-3 kinase (p85), caveolins or the adaptor protein Shc. See text for details.

Figure 2. Updated model of ER pharmacology

The overall conformation of ER is influenced by the nature of the ligand to which it is bound; an activity which enables the differential interaction of the receptor with functionally distinct coregulators. Pure agonists facilitate the interaction of the receptor with coactivators (CoA) and thus the cellular response to an ER-agonist complex will be determined by the relative expression level of functionally distinct coregulators in different target tissues. Antagonists, on the other hand allow the receptor to interact with only corepressors (CoR). Selective estrogen receptor modulators (SERMs) permit the bound ERs to interact with different subsets of coactivators and corepressors, permitting these drugs to elicit different activities in different tissues.

Figure 3. A novel mechanism describing ER action in bone

Some of the protective actions of estrogens in bone can be attributed to its ability to upregulate the expression of Small Heterodimeric Partner (SHP) in preosteoblasts. This protein functions as a negative regulator of the LXR/RXR heterodimer, which itself is a positive regulation of TNFα expression. Interestingly, by functioning as both an inhibitor of ER and an activator of LXR the cholesterol metabolite 27-hydroxycholesterol (27HC) can positively upregulate the expression of genes involved in osteoclastogenesis. See text for details.