title: Preservation of high-fat diet-induced femoral trabecular bone loss through genetic target of TNF-α.
abstract: Obesity and osteoporosis are two common chronic diseases, however, the basis for the correlation between them remains largely unknown. The pro-inflammation cytokine tumor necrosis factor-alpha (TNF-α) plays important roles in lipid and bone metabolisms, which may be a good candidate in the correlation between obesity and osteoporosis. We investigated the pathological roles of TNF-α in high-fat diet (HFD)-induced bone loss. Wild-type (WT) mice and TNF-α knockout (TNF-α(-/-)) mice were fed with the standard diet or the HFD for 12 weeks. Bone marrow stromal cells (BMSCs) from both genotypes were induced to differentiate into osteoblasts and treated with palmitic acid (PA). Bone mass and microstructure of femurs were evaluated by micro-CT. Lipid and bone metabolisms were investigated by histological and plasma analyses, and real-time PCR. On the HFD, both TNF-α(-/-) and WT mice presented notable visceral obesity, dyslipidemia. Adipogenesis and osteoclastogenesis were enhanced, while osteoblastogenesis was reduced in both genotypes. However, the changes were significantly different between TNF-α(-/-) and WT mice after the HFD. The gain of body and fat-pad weight was less and adipocyte area was smaller by 22 % in TNF-α(-/-) mice. Osteoclast numbers and plasma CTX level were lower by 40 % and by 23 % in TNF-α(-/-) mice. There were more ALP positive cells in the PA-treated TNF-α(-/-) BMSCs. mRNA expression of PPAR-γ was lower while that of Runx2 was higher in the bone from TNF-α(-/-) HFD group and in the PA-treated TNF-α(-/-) BMSCs, compared to WT on the same treatment. Furthermore, femoral trabecular bone mass and trabecular bone number were significantly decreased in WT mice on the HFD, whereas they were increased by 1.56-fold and 1.53-fold, respectively, in TNF-α(-/-) mice on the same diet (P < 0.05). Our results demonstrated that TNF-α gene knockout retained HFD-induced femoral trabecular bone loss mainly by suppressing adipogenesis and osteoclastogenesis, and enhancing osteoblastogenesis, which suggests that TNF-α plays a critical role in the development of HFD-related bone metabolic disorders and it may be a new potential therapeutic target for obesity-related bone loss.
authors.affiliation: Laboratory of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, 610041, Sichuan, People's Republic of China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiao
authors.initials: X
authors.lastname: Ji
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.forename: Xijie
authors.initials: X
authors.lastname: Yu
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D004041:Dietary Fats / Q000009:adverse effects*; D005269:Femur / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D014409:Tumor Necrosis Factor-alpha