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Potential mechanism of estrogen-mediated decrease in bone formation: estrogen increases production of inhibitory
M Kassem1, R Okazaki, D De León
1Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN 55905, USA.
Proceedings of the Association of American Physicians
|March 1, 1996
Summary
Estrogen reduces bone formation by increasing inhibitory insulin-like growth factor-binding protein-4 (IGFBP-4) in osteoblastic cells. This mechanism, mediated by estrogen receptors, enhances IGFBP-4 production and reduces its degradation, opposing cell growth.
Area of Science:
- Endocrinology
- Bone Biology
- Cellular Signaling
Background:
- Estrogen plays a critical role in bone health, and its decline is associated with osteoporosis.
- The precise mechanisms by which estrogen influences bone formation are complex and involve interactions with growth factor systems.
- Osteoblastic cells are key regulators of bone formation and express estrogen receptors.
Purpose of the Study:
- To investigate the hypothesis that estrogen decreases bone formation by inhibiting the insulin-like growth factor (IGF) paracrine/autocrine system in osteoblasts.
- To elucidate the role of IGF-binding proteins (IGFBPs) in mediating estrogen's effects on osteoblastic cells.
Main Methods:
- Utilized a human osteoblastic cell line (hFOB/ER9) expressing high levels of estrogen receptors.
- Measured [3H]thymidine uptake to assess cell proliferation following 17 beta-estradiol (E2) treatment.
- Quantified IGFBP-4 and IGFBP-3 mRNA and protein levels using RT-PCR and Western blotting.
- Assessed the effect of E2 on IGFBP-4 proteolysis and cell proliferation in response to recombinant IGFBP-4.
Main Results:
- 17 beta-estradiol (E2) treatment significantly decreased osteoblastic cell proliferation in a dose-dependent manner.
- E2 increased both IGFBP-4 mRNA and protein levels, while IGFBP-3 levels remained unchanged.
- E2 treatment attenuated IGF-dependent proteolysis of IGFBP-4, increasing the availability of this inhibitory protein.
- A pure anti-estrogen (ICI 182,780) blocked the effects of E2 on cell proliferation and IGFBP-4 levels.
- Exogenous IGFBP-4 inhibited osteoblastic cell proliferation, mimicking the effect of E2.
Conclusions:
- Estrogen decreases bone formation by upregulating the production and reducing the degradation of inhibitory IGFBP-4 in osteoblastic cells.
- This action of estrogen, mediated via estrogen receptors, opposes the mitogenic effects of IGFs on osteoblastic cells.
- The modulation of IGFBP-4 by estrogen is a significant mechanism contributing to estrogen's in vivo effects on bone formation.