scholarly journals Tumor Necrosis Factor-α Mediates Osteopenia Caused by Depletion of Antioxidants

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 113-118 ◽  
Author(s):  
C. J. Jagger ◽  
J. M. Lean ◽  
J. T. Davies ◽  
T. J. Chambers

We recently found that estrogen deficiency leads to a lowering of thiol antioxidant defenses in rodent bone. Moreover, administration of agents that increase the concentration in bone of glutathione, the main intracellular antioxidant, prevented estrogen-deficiency bone loss, whereas depletion of glutathione by buthionine sulfoximine (BSO) administration provoked substantial bone loss. It has been shown that the estrogen-deficiency bone loss is dependent on TNFα signaling. Therefore, a model in which estrogen deficiency causes bone loss by lowering antioxidant defenses predicts that the osteopenia caused by lowering antioxidant defenses should similarly depend on TNFα signaling. We found that the loss of bone caused by either BSO administration or ovariectomy was inhibited by administration of soluble TNFα receptors and abrogated in mice deleted for TNFα gene expression. In both circumstances, lack of TNFα signaling prevented the increase in bone resorption and the deficit in bone formation that otherwise occurred. Thus, depletion of thiol antioxidants by BSO, like ovariectomy, causes bone loss through TNFα signaling. Furthermore, in ovariectomized mice treated with soluble TNFα receptors, thiol antioxidant defenses in bone remained low, despite inhibition of bone loss. This suggests that the low levels of antioxidants in bone seen after ovariectomy are the cause, rather than the effect, of the increased resorption. These experiments are consistent with a model for estrogen-deficiency bone loss in which estrogen deficiency lowers thiol antioxidant defenses in bone cells, thereby increasing reactive oxygen species levels, which in turn induce expression of TNFα, which causes loss of bone.

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lin Chen ◽  
Shao Cheng ◽  
Kanghui Sun ◽  
Jing Wang ◽  
Xinhua Liu ◽  
...  

Abstract Background Macrophages and inflammatory cytokines play important roles in bone fracture healing. However, the expression patterns of macrophages and inflammatory cytokines during fracture healing under the condition of postmenopausal osteoporosis have not been fully revealed. Methods Tibia transverse fracture was established 12 weeks after ovariectomy or sham operation in 16-week old female mice. Tibias were harvested before fracture or 1, 3, 5, 7, 14, 21, 28 days after fracture for radiological and histological examinations. M1/M2 inflammatory macrophages, osteal macrophages and gene expressions of tumor necrosis factor-α, interleukin-6, interleukin-1β and macrophage conversion related molecules in the fracture haematoma or callus were also detected. Results The processes of fracture healing, especially the phases of endochondral ossification and callus remodeling, were delayed in ovariectomized mice. The expressions of tumor necrosis factor-α and interleukin-6, but not interleukin-1β, in the fracture haematoma or callus were disturbed. Expressions of tumor necrosis factor-α were decreased at 1, 14 and 21 days post-fracture (DPF), and were increased at 3, 5 and 7 DPF. Interleukin-6 expressions at 1, 3 and 21 DPF were significantly increased. We found the decreases in M1 and M2 macrophages at 1 DPF of the initial inflammatory stage. M2 macrophages at 14 DPF of the middle stage and osteal macrophages at 14, 21 and 28 DPF of the middle and late stages of fracture healing were also reduced in ovariectomized mice. Conclusions The expressions of macrophages and inflammatory cytokines were impaired in ovariectomized mice, which might contribute partially to poor fracture healing.


2020 ◽  
Vol 21 (24) ◽  
pp. 9479
Author(s):  
Nobuto Nagao ◽  
Hiroki Wakabayashi ◽  
Gaku Miyamura ◽  
Sho Kato ◽  
Yohei Naito ◽  
...  

This study aimed to evaluate skeletal pain associated with osteoporosis and to examine the inhibitory effects of cytotoxic T lymphocyte-associated antigen-4Ig (CTLA-4Ig) administration in ovariectomized (OVX) mice. Eight-week-old female ddY mice were assigned to three groups: sham-operated mice (SHAM) treated with vehicle, OVX mice treated with vehicle (OVX), and OVX mice treated with CTLA-4Ig (CTLA-4Ig). Vehicle or CTLA-4Ig was injected intraperitoneally, starting immediately after surgery. After 4 weeks of treatment, mechanical sensitivity was examined, and the bilateral hind limbs were removed and evaluated by micro-computed tomography, immunohistochemical analyses, and messenger RNA expression analysis. Ovariectomy induced bone loss and mechanical hyperalgesia in the hindlimbs. CTLA-4Ig treatment prevented bone loss in the hindlimbs compared to vehicle administration in the OVX group. Moreover, mechanical hyperalgesia was significantly decreased in the CTLA-4Ig treatment group in comparison to the OVX group. The expression levels of tumor necrosis factor-α (TNF-α) and sclerostin (SOST), as well as the number of osteoclasts, were increased, and the expression level of Wnt-10b was decreased in the OVX group compared with the SHAM group, whereas these parameters were improved in the CTLA-4Ig group compared with the OVX group. The novelty of this research is that CTLA-4Ig administration prevented bone loss and mechanical hyperalgesia induced by ovariectomy in the hindlimbs.


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