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A crucial role for thiol antioxidants in estrogen-deficiency bone loss
Jenny M. Lean, … , Zoë L. Urry, Timothy J. Chambers
Jenny M. Lean, … , Zoë L. Urry, Timothy J. Chambers
Published September 15, 2003
Citation Information: J Clin Invest. 2003;112(6):915-923. https://doi.org/10.1172/JCI18859.
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Article Bone Biology

A crucial role for thiol antioxidants in estrogen-deficiency bone loss

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Abstract

The mechanisms through which estrogen prevents bone loss are uncertain. Elsewhere, estrogen exerts beneficial actions by suppression of reactive oxygen species (ROS). ROS stimulate osteoclasts, the cells that resorb bone. Thus, estrogen might prevent bone loss by enhancing oxidant defenses in bone. We found that glutathione and thioredoxin, the major thiol antioxidants, and glutathione and thioredoxin reductases, the enzymes responsible for maintaining them in a reduced state, fell substantially in rodent bone marrow after ovariectomy and were rapidly normalized by exogenous 17-β estradiol. Moreover, administration of N-acetyl cysteine (NAC) or ascorbate, antioxidants that increase tissue glutathione levels, abolished ovariectomy-induced bone loss, while L-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis, caused substantial bone loss. The 17-β estradiol increased glutathione and glutathione and thioredoxin reductases in osteoclast-like cells in vitro. Furthermore, in vitro NAC prevented osteoclast formation and NF-κB activation. BSO and hydrogen peroxide did the opposite. Expression of TNF-α, a target for NF-κB and a cytokine strongly implicated in estrogen-deficiency bone loss, was suppressed in osteoclasts by 17-β estradiol and NAC. These observations strongly suggest that estrogen deficiency causes bone loss by lowering thiol antioxidants in osteoclasts. This directly sensitizes osteoclasts to osteoclastogenic signals and entrains ROS-enhanced expression of cytokines that promote osteoclastic bone resorption.

Authors

Jenny M. Lean, Julie T. Davies, Karen Fuller, Christopher J. Jagger, Barrie Kirstein, Geoffrey A. Partington, Zoë L. Urry, Timothy J. Chambers

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Figure 1

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Estrogen maintains thiol antioxidant system in rat bone marrow. (a and b...
Estrogen maintains thiol antioxidant system in rat bone marrow. (a and b) Ovariectomy (ovx) decreased while 17-β estradiol (βE2) (10 μg/kg) restored glutathione (nmol/mg protein) and glutathione reductase (mU/mg protein) in bone marrow (r, reduced glutathione; o, oxidized glutathione). (c and d) Ovariectomy suppressed thioredoxin (nmol/mg protein) and thioredoxin reductase (mU/mg protein) in bone marrow, while 17-β estradiol normalized both. (e) 17-α estradiol (αE2) was without significant effect on glutathione levels. Thiol levels and enzymes were also measured in liver and spleen and did not differ significantly between groups. *P < 0.05 versus all other groups. Data expressed as mean ± SEM; n = 6 per group. These experiments were repeated twice in mice and similarly showed significant changes in the levels of antioxidant defense components in bone marrow after ovariectomy, which were normalized by 17-β estradiol.
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