Sex steroids and bone.

By S. Manolagas, S. Kousteni, R. Jilka. Recent Progress in Hormone Research, 2002

790 citations recorded by the source corpus.

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.

Subfields: Genetics, Oncology, Orthopedics and Sports Medicine

View Paper: https://www.semanticscholar.org/paper/ed7f2c8f7e0ec89e6fba0d26fcc16551ebd86e59

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Stephen Honig
2. P. Rackoff
3. C. Sawyers
4. S. Manolagas

In Oncology

1. Stephen Honig
2. P. Rackoff
3. G. Karsenty
4. S. Manolagas
5. C. Sawyers
6. P. Ducy
7. S. Khosla
8. R. Jilka

In Orthopedics and Sports Medicine

1. Stephen Honig
2. P. Rackoff
3. S. Manolagas

Citations in the corpus

• The Female Athlete Triad (2007, positive): “Uncoupling of bone turnover with a reduction of bone formation and an increase in bone resorption can cause irreversible reductions in BMD (35).”
• Molecular determinants of resistance to antiandrogen therapy (2004, background): “Thus, the previously reported nongenotropic effects of androgen receptor on bone growth and prostate cancer cell surviva”
• From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. (2010, background): “Consistent with this evidence, estrogens protect the adult skeleton against bone loss by slowing the rate of bone remodeling (turnover) and by maintaining a focal balance between bone formation and resorption (1, 138, 139).”
• Endocrine regulation of male fertility by the skeleton. (2011, positive): “To date the study of the interplay between gonads and bone has focused on the mechanism whereby sex steroid hormones affect bone mass accrual (Manolagas et al., 2002; Nakamura et al., 2007).”