TNF-α upregulates sclerostin expression in obese mice fed a high-fat diet.
Sclerostin decreases bone mass by antagonizing the Wnt signaling pathway. We examined whether obesity-induced bone loss is associated with the expression of sclerostin. Five-week-old male mice were assigned to one of two groups (n = 10 each) and fed either a control diet (10% kcal from fat; CON) or a high-fat diet (60% kcal from fat; HF) for 12 weeks. Thex final body weight and whole body fat mass of the HF mice were higher than those of the CON mice. The distal femur cancellous bone mineral density and bone formation rate was lower in HF mice than in CON mice. The percent erosion surface was higher in the HF mice than the CON mice. The serum levels and femoral osteocytic protein expression levels of tumor necrosis factor-α (TNF-α) were significantly higher in HF mice than in CON mice. Sclerostin mRNA levels and osteocytic sclerostin protein levels in femoral cortex were also higher in HF mice than in CON mice. Sclerostin expression in MLO-Y4 osteocytes increased with TNF-α treatment, and TNF-α-induced sclerostin expression was blocked by the inhibition of NF-κB activation. Chromatin immunoprecipitation and a luciferase reporter assay demonstrated that NF-κB directly binds to the NF-κB binding elements on the mouse sost promoter and stimulates sclerostin expression. These results support a model in which, in the context of obesity or other inflammatory diseases that increase the production of TNF-α, TNF-α upregulates the expression of sclerostin through NF-κB signaling pathway, thus contributing to bone loss.
Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea; Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwondo, Korea.
Kyunghwa
K
Baek
Hyo Rin
HR
Hwang
Hyun-Jung
HJ
Park
Arang
A
Kwon
Abdul S
AS
Qadir
Seong-Hee
SH
Ko
Kyung Mi
KM
Woo
Hyun-Mo
HM
Ryoo
Gwan-Shik
GS
Kim
Jeong-Hwa
JH
Baek
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001823:Body Composition / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002460:Cell Line; D004041:Dietary Fats / Q000009:adverse effects*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009765:Obesity; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D048868:Adaptor Proteins, Signal Transducing; D004041:Dietary Fats; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; C486030:Sost protein, mouse; D014409:Tumor Necrosis Factor-alpha