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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 Article has an altmetric score of 6

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 2

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Ascorbate and NAC prevent bone loss in ovariectomized mice. (a–g) Ascorb...
Ascorbate and NAC prevent bone loss in ovariectomized mice. (a–g) Ascorbate (2 mmol/kg/day) prevents ovariectomy-induced bone loss in mice. (a) Representative images of microscope sections of femora from mice subjected to sham ovariectomy (sham) or ovariectomy (ovx) and treated for 2 weeks with ascorbate (1 nmol/kg twice daily) or vehicle. (b–g) Histomorphometric analysis shows that ascorbate prevented ovariectomy-induced bone loss (b). Indices of bone resorption (c–e) (osteoclast number per millimeter of bone surface; percentage of bone surface covered by osteoclasts; percentage of bone surface that shows scalloped, eroded appearance) were increased by ovariectomy and suppressed by ascorbate. Ascorbate also normalized (f and g) the number of osteoblasts per millimeter of bone surface and the percentage of bone surface covered by osteoblasts to sham levels. Total glutathione in bone marrow fell significantly (P < 0.05) from 32 ± 5 nmol/mg protein in controls to 22 ± 1.2 nmol/mg protein in ovariectomized mice and was increased by ascorbate to 54 ± 12.3 nmol/mg protein. (h–m) NAC (100 mg/kg/day) prevents ovariectomy-induced bone loss in mice. Indices of bone resorption and bone formation show that while ovariectomy caused a reduction in bone volume (h), this was prevented by NAC. NAC also normalized the number of osteoclasts per millimeter of the bone surface (i), the percentage of bone surface that was covered by osteoclasts (j), and the percentage of bone surface that showed a crenated, eroded surface characteristic of osteoclastic activity (k). NAC also reversed the ovariectomy-induced increase in osteoblast numbers (l) and the percentage of surface that was covered by osteoblasts (m). *P < 0.05 versus other groups. Data expressed as mean ± SEM. Oc, osteoclast; ES/BS(%), percentage of bone surface that shows an eroded surface appearance; Ob, osteoblast.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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