Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1.
Tumor necrosis factor inhibits mesenchymal stem cell differentiation into osteoblasts via the ubiquitin E3 ligase Wwp1.
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DOI：
10.1002/stem.703
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发表时间：
2011-10
期刊：
影响因子：
5.2
通讯作者：
Xing, Lianping
中科院分区：
文献类型：
--
作者：
Zhao, Lan;Huang, Jian;Zhang, Hengwei;Wang, Yi;Matesic, Lydia E.;Takahata, Masahiko;Awad, Hani;Chen, Di;Xing, Lianping
慢性炎症性疾病，如类风湿关节炎的患者，由于肿瘤坏死因子诱导的骨吸收增加和骨形成减少的共同作用，经常发生骨质疏松症。为了测试TNF是否通过影响间充质干细胞（MSCs）向成骨细胞的转化和分化来抑制骨形成，我们检测了TNF转基因（TNF- tg）小鼠（一种慢性炎性关节炎模型）MSCs的成骨潜能。采用抗cd45抗体包被磁珠的负选择方法从骨髓基质细胞中分离出msc富集细胞。通过FACS和细胞分化实验证实了间充质干细胞表面标记物的表达谱以及CD45−细胞的成骨、软骨和脂肪特性。TNF-Tg小鼠的msc富集CD45−细胞形成成纤维细胞和ALP+菌落数量显著减少，成骨细胞标记基因表达减少。由于TNF可能上调泛素连接酶，从而负向调节成骨细胞分化，我们检测了几种泛素连接酶的表达水平，发现在TNF- tg小鼠的msc富集CD45−细胞中Wwp1的表达显著增加。Wwp1敲低可挽救TNF-Tg CD45−细胞的成骨细胞分化受损。Wwp1促进JunB的泛素化和降解，JunB是AP-1转录因子，积极调节成骨细胞分化。在野生型小鼠中注射TNF导致MSCs成骨细胞分化减少，JunB泛素化增加，而在Wwp1−/−小鼠中，JunB泛素化被完全阻断。因此，慢性暴露于TNF后，Wwp1靶向JunB在MSCs中泛素化和降解，抑制MSCs中的Wwp1可能是通过促进其向成骨细胞分化来限制炎症介导的骨质疏松症的新机制。
Patients with chronic inflammatory disorders, such as rheumatoid arthritis, often have osteoporosis due to a combination of Tumor necrosis factor-induced increased bone resorption and reduced bone formation. To test if TNF inhibits bone formation by affecting the commitment and differentiation of mesenchymal stem cells (MSCs) into osteoblasts, we examined the osteogenic potential of MSCs from TNF transgenic (TNF-Tg) mice, a model of chronic inflammatory arthritis. MSC-enriched cells were isolated from bone marrow stromal cells using negative selection with anti-CD45 antibody coated magnetic beads. The expression profile of MSC surface markers the osteogenic, chondrogenic, and adipogenic properties of CD45− cells were confirmed by FACS and cell differentiation assays. MSC-enriched CD45− cells from TNF-Tg mice formed significantly decreased numbers of fibroblast and ALP+ colonies and had a decreased expression of osteoblast marker genes. As TNF may upregulate ubiquitin ligases, which negatively regulate osteoblast differentiation, we examined the expression levels of several ubiquitin ligases and found that Wwp1 expression was significantly increased in MSC-enriched CD45− cells of TNF-Tg mice. Wwp1 knockdown rescued impaired osteoblast differentiation of TNF-Tg CD45− cells. Wwp1 promotes ubiquitination and degradation of JunB, an AP-1 transcription factor that positively regulates osteoblast differentiation. Injection of TNF into wild-type mice resulted in decreased osteoblast differentiation of MSCs and increased JunB ubiquitination, which was completely blocked in Wwp1−/− mice. Thus, Wwp1 targets JunB for ubiquitination and degradation in MSCs after chronic exposure to TNF, and inhibition of Wwp1 in MSCs could be a new mechanism to limit inflammation-mediated osteoporosis by promoting their differentiation into osteoblasts.
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影响因子：
2.7
作者：
Dudics, Valeria;Kunstar, Aliz;Uher, Ferenc
通讯作者：
Uher, Ferenc
DOI：
10.1109/oceans.2007.4449207
发表时间：
2007-01-01
期刊：
OSTEOIMMUNOLOGY
影响因子：
--
作者：
Jones, Dallas C.;Wein, Marc N.;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
影响因子：
6.2
作者：
Walsh, Nicole C.;Reinwald, Susan;Gravallese, Ellen M.
通讯作者：
Gravallese, Ellen M.
影响因子：
4.8
作者：
Gilbert, L;He, XF;Nanes, MS
通讯作者：
Nanes, MS
DOI：
10.1073/pnas.0510664103
发表时间：
2006-02-07
影响因子：
11.1
作者：
Gallagher, E;Gao, M;Karin, M
通讯作者：
Karin, M