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The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice
R B Kimble1, S Bain, R Pacifici
1Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, Missouri, USA.
Abstract:
Considerable evidence supports the hypothesis that estrogen prevents bone loss by blocking the bone marrow cell production of pro-osteoclastogenic cytokines. However, controversy remains on the role of candidate factors, such as tumor necrosis factor (TNF) and interleukin-6 (IL-6). To investigate the contribution of these cytokines to the pathogenesis of ovariectomy (OVX)-induced bone loss, OVX mice were treated with either TNF binding protein (TNFbp), an inhibitor of TNF, the anti-(IL-6) antibody (Ab) 20F3, or estrogen for the first 2 weeks after surgery. OVX caused a rapid decrease in trabecular bone volume (TBV) and an increase in in vivo bone resorption, as assessed by bone histomorphometry. Treatment with TNFbp completely prevented bone loss and the increase in both osteoclast formation and bone resorption induced by OVX, but had no effects in sham-operated controls. In contrast, treatment with anti-IL-6 antibody failed to prevent bone loss, and the increase in bone resorption and osteoclastogenesis induced by OVX. These data demonstrate that in nongenetically manipulated mice, the estrogen-regulated cytokine that plays a central role in the mechanism by which estrogen deficiency causes bone loss is not IL-6, but rather TNF.
Insights
Estrogen deficiency causes bone loss by increasing tumor necrosis factor (TNF), not interleukin-6 (IL-6). Inhibiting TNF prevents bone loss in ovariectomized mice, highlighting TNF's crucial role.
Area of Science:
- Endocrinology
- Bone Biology
- Immunology
Background:
- Estrogen deficiency, often seen post-menopause, leads to bone loss.
- Cytokines like tumor necrosis factor (TNF) and interleukin-6 (IL-6) are implicated in estrogen's bone-protective effects.
- The precise role of TNF versus IL-6 in ovariectomy (OVX)-induced bone loss remains debated.
Purpose of the Study:
- To investigate whether TNF or IL-6 is the primary mediator of estrogen's protective effect against bone loss.
- To determine the contribution of TNF and IL-6 to the pathogenesis of OVX-induced bone loss in mice.
Main Methods:
- Ovariectomized (OVX) mice were treated with TNF binding protein (TNFbp), an anti-IL-6 antibody (20F3), or estrogen for two weeks post-surgery.
- Bone histomorphometry was used to assess changes in trabecular bone volume (TBV) and in vivo bone resorption.
Main Results:
- OVX induced significant bone loss and increased bone resorption, evidenced by decreased TBV and elevated osteoclast activity.
- Treatment with TNFbp completely prevented OVX-induced bone loss, osteoclast formation, and bone resorption.
- Anti-IL-6 antibody treatment did not prevent bone loss or alter OVX-induced increases in bone resorption and osteoclastogenesis.
Conclusions:
- Tumor necrosis factor (TNF), not interleukin-6 (IL-6), is the key estrogen-regulated cytokine responsible for mediating bone loss following estrogen deficiency in this model.
- Targeting TNF represents a potential therapeutic strategy to prevent or treat bone loss associated with estrogen deficiency.