Sex Steroids and Bone

Abstract

The adult skeleton is periodically remodeled by temporary anatomic structures that comprise juxtaposed osteoclast and osteoblast teams and replace old bone with new. Estrogens and androgens slow the rate of bone remodeling and protect against bone loss. Conversely, loss of estrogen leads to increased rate of remodeling and tilts the balance between bone resorption and formation in favor of the former. Studies from our group during the last 10 years have elucidated that estrogens and androgens decrease the number of remodeling cycles by attenuating the birth rate of osteoclasts and osteoblasts from their respective progenitors. These effects result, in part, from the transcriptional regulation of genes responsible for osteoclastogenesis and mesenchymal cell replication and/or differentiation and are exerted through interactions of the ligand-activated receptors with other transcription factors. However, increased remodeling alone cannot explain why loss of sex steroids tilts the balance of resorption and formation in favor of the former. Estrogens and androgens also exert effects on the lifespan of mature bone cells: pro-apoptotic effects on osteoclasts but anti-apoptotic effects on osteoblasts and osteocytes. These latter effects stem from a heretofore unexpected function of the classical "nuclear" sex steroid receptors outside the nucleus and result from activation of a Src/Shc/extracellular signal-regulated kinase signal transduction pathway probably within preassembled scaffolds called caveolae. Strikingly, estrogen receptor (ER) alpha or beta or the androgen receptor can transmit anti-apoptotic signals with similar efficiency, irrespective of whether the ligand is an estrogen or an androgen. More importantly, these nongenotropic, sex-nonspecific actions are mediated by the ligand-binding domain of the receptor and can be functionally dissociated from transcriptional activity with synthetic ligands. Taken together, these lines of evidence strongly suggest that, in sex steroid deficiency, loss of transcriptional effects may be responsible for the increased osteoclastogenesis and osteoblastogenesis and thereby the increased rate of bone remodeling. Loss of nongenotropic anti-apoptotic effects on mature osteoblasts and osteocytes, in combination with an opposite effect on the lifespan of mature osteoclasts, may be responsible for the imbalance between formation and resorption and the progressive loss of bone mass and strength. Elucidation of the dual function of sex steroid receptors has important pathophysiologic and pharmacologic implications. Specifically, synthetic ligands of the ER that can evoke the nongenotropic but not the genotropic signal may be bone anabolic agents, as opposed to natural estrogens or selective estrogen receptor modulators that are antiresorptive agents. The same ligands may also circumvent the side effects associated with conventional hormone replacement therapy. 385

p38 MAPK Regulates IL‐1β Induced IL‐6 Expression Through mRNA Stability in Osteoblasts

“…Several investigators have demonstrated that both estrogens and androgens suppress the production of IL-6 as well as the expression of the two subunits of the IL-6 receptor, IL-6R and gp130, in cells of the bone marrow stromal/osteoblastic lineage (1,14,34). Similar results were obtained subsequently by others in rats as well as in humans, in the bone marrow and in the peripheral blood (35,51). Importantly, it was shown that neutralization of IL-6 with antibodies or knockout of the IL-6 gene in mice prevents the upregulation of granulocyte macrophage-colony stimulating factor (GM-CSF) in the marrow, and the expected increase of osteoclast numbers in trabecular bone sections; and also protects the loss of bone following loss of sex steroids (1,21).…”

Depression induces bone loss through stimulation of the sympathetic nervous system

“…The respective locomotor activity (number of line crossings in the open-field test) was 162.5 Ϯ 9.3 and 149.9 Ϯ 8.3 (mean Ϯ SEM) (P Ͼ 0.1). Sexual activity and sex hormone secretion are reduced in depressed subjects (20), and sex hormones depletion is a major cause of bone loss (21). Hence, to elucidate the pathways mediating the skeletal effect of stress-induced depression, we initially measured serum testosterone levels, which remained unaltered in mice exposed to CMS as compared with nonstressed controls (Fig.…”

Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor

“…Binding of androgen induces receptor nuclear translocation, dimerization, binding to DNA, and recruitment of transcriptional machinery to activate downstream signaling. Additionally, in a nongenotropic signaling pathway, AR is also capable of binding and activating c-Src kinase through a polyproline region to stimulate prostate cancer cell proliferation and bone growth (24)(25)(26). The stability of AR is also reported to be modulated by AKT through phosphorylation (13,14,17,18).…”