TNF-α mediates the stimulation of sclerostin expression in an estrogen-deficient condition.
Although recent clinical studies have suggested a possible role for sclerostin, a secreted Wnt antagonist, in the pathogenesis of postmenopausal osteoporosis, the detailed mechanisms how estrogen deficiency regulates sclerostin expression have not been well-elucidated. Bilateral ovariectomy or a sham operation in female C57BL/6 mice and BALB/c nude mice was performed when they were seven weeks of age. The C57BL/6 mice were intraperitoneally injected with phosphate-buffered serum (PBS), 5 μg/kg β-estradiol five times per week for three weeks, or 10 mg/kg TNF-α blocker three times per week for three weeks. Bony sclerostin expression was assessed by immunohistochemistry staining in their femurs. The activity and expression of myocyte enhancer factors 2 (MEF2), which is essential for the transcriptional activation of sclerostin, in rat UMR-106 osteosarcoma cells were determined by luciferase reporter assay and western blot analysis, respectively. Bony sclerostin expression was stimulated by estrogen deficiency and it was reversed by estradiol supplementation. When the UMR-106 cells were treated with well-known, estrogen-regulated cytokines, only TNF-α, but not IL-1 and IL-6, increased the MEF2 activity. Consistently, TNF-α also increased the nuclear MEF2 expression. Furthermore, the TNF-α blocker prevented the stimulation of bony sclerostin expression by ovariectomy. We also found that there was no difference in sclerostin expression between ovariectomized nude mice and sham-operated nude mice. In conclusion, these results suggest that TNF-α originating from T cells may be at least in part responsible for stimulating the sclerostin expression observed in an estrogen-deficient condition.
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap2-Dong, Seoul, Republic of Korea.
Beom-Jun
BJ
Kim
Sung Jin
SJ
Bae
Sun-Young
SY
Lee
Young-Sun
YS
Lee
Ji-Eun
JE
Baek
Sook-Young
SY
Park
Seung Hun
SH
Lee
Jung-Min
JM
Koh
Ghi Su
GS
Kim
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018006:Myogenic Regulatory Factors / Q000494:pharmacology; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D051381:Rats; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D004967:Estrogens; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D007376:Interleukin-2; D018006:Myogenic Regulatory Factors; C486030:Sost protein, mouse; D014409:Tumor Necrosis Factor-alpha