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.
J Cell Physiol. 2014 May;229(5):640-50. doi: 10.1002/jcp.24487.
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.
骨硬化蛋白通过拮抗 Wnt 信号通路来减少骨量。我们研究了肥胖诱导的骨丢失是否与骨硬化蛋白的表达有关。将 5 周龄雄性小鼠分为两组（每组 10 只），分别给予对照饮食（脂肪供能 10%）或高脂饮食（脂肪供能 60%）12 周。与 CON 组相比，HF 组小鼠的最终体重和全身脂肪量更高。HF 组小鼠的远端股骨松质骨骨密度和骨形成率更低，侵蚀表面百分比更高。与 CON 组相比，HF 组小鼠的血清水平和股骨破骨细胞蛋白表达水平的肿瘤坏死因子-α（TNF-α）显著升高。HF 组小鼠的骨硬化蛋白 mRNA 水平和股骨皮质的破骨细胞骨硬化蛋白蛋白水平也高于 CON 组。MLO-Y4 破骨细胞中骨硬化蛋白的表达随着 TNF-α 处理而增加，并且 NF-κB 激活的抑制阻断了 TNF-α 诱导的骨硬化蛋白表达。染色质免疫沉淀和荧光素酶报告基因分析表明，NF-κB 直接结合到小鼠 sost 启动子上的 NF-κB 结合元件上，并刺激骨硬化蛋白的表达。这些结果支持了这样一种模型，即在肥胖或其他增加 TNF-α 产生的炎症性疾病的情况下，TNF-α 通过 NF-κB 信号通路上调骨硬化蛋白的表达，从而导致骨丢失。
