Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production.
To analyze how estrogen blocks osteoclastogenesis, we investigated the effects of ovariectomy on osteoclast (OC) formation in co-cultures of purified OC precursors and purified stromal cells (SC). OC formation was higher in co-cultures containing SC from ovariectomized mice than in those containing SC from sham-operated mice, thus suggesting that estrogen regulates osteoclastogenesis by targeting SC. Ovariectomy also increased the mononuclear cell secretion of interleukin (IL)-1) and tumor necrosis factor (TNF) and the SC production of macrophage colony-stimulating factor (MCSF). Osteoclastogenesis and SC production of M-CSF were not blocked by in vitro estrogen treatment but were decreased by in vivo treatment of donor mice with either estrogen or a combination of the IL-1 inhibitor, IL-1 receptor antagonist, and the TNF inhibitor, TNF binding protein. IL-1 and TNF production were also blocked by in vivo estrogen treatment, demonstrating that the increased bone marrow levels of IL-1 and TNF characteristic of ovariectomized mice induce the formation of a SC population characterized by a high production of M-CSF and increased pro-osteoclastogenic activity. Since in co-cultures of SC and OC precursors M-CSF levels correlated with OC production (r = 0.7, p < 0.0001), the data also indicate that the pro-osteoclastogenic activity of SC is proportional to their secretion of M-CSF. The ability of estrogen to decrease SC production of M-CSF and the pro-osteoclastogenic activity of these cells by regulating IL-1 and TNF production is a previously undescribed mechanism by which estrogen down-regulates osteoclastogenesis.
Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes/Jewish Hospital, St. Louis, Missouri 63110, USA. Pacifici@imgate.wustl.edu
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RB
Kimble
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Srivastava
F P
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Ross
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A
Matayoshi
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Pacifici
D000818:Animals; D004967:Estrogens / Q000172:deficiency / Q000502:physiology*; D005260:Female; D007375:Interleukin-1 / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D010010:Osteoclasts / Q000166:cytology*; D010052:Ovariectomy; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D004967:Estrogens; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor