Ubiquitin e3 ligase itch negatively regulates osteoblast differentiation from mesenchymal progenitor cells.
Ubiquitin e3 ligase itch negatively regulates osteoblast differentiation from mesenchymal progenitor cells.
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DOI：
10.1002/stem.1395
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发表时间：
2013-08
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：
Zhang, Hengwei;Xing, Lianping
Itch 是一种 HECT 家族 E3 连接酶，通过调节靶蛋白的泛素化和蛋白酶体降解来影响多种细胞功能。然而，瘙痒在成骨细胞中的作用尚未得到研究。我们报告说，Itch−/− 小鼠的骨体积、成骨细胞数量和骨形成率显着增加。使用来自 Itch−/− 小鼠和 WT 同窝小鼠的骨髓基质细胞作为骨髓间充质前体细胞 (BM-MPC)，我们发现来自 Itch−/− 小鼠的 BM-MPC 具有数量相匹配的表达间充质干细胞标记物的细胞。然而，Itch−/− BM-MPC 在体外培养中生长更快，形成更多 CFU-F 间充质集落，并表现出成骨细胞分化增加和脂肪生成减少。重要的是，与 WT 细胞相比，Itch−/− 间充质集落细胞在受体小鼠的胫骨缺损中形成了明显更多的新骨。当蛋白酶体功能完整时，Itch−/− BM-MPC 中 JunB（一种正调节成骨细胞分化的 AP-1 转录因子）的表达水平显着增加。相比之下，当蛋白酶体功能被阻断时，Itch−/− 细胞中泛素化 JunB 蛋白的量显着减少。 WT Itch 的过表达，而非 Itch 连接酶失活突变体，挽救了 Itch−/− BM-MPC 的分化缺陷。 Itch−/− BM-MPC 在免疫调节中与 WT 细胞具有相似的作用。因此，Itch 通过调节正性成骨细胞调节剂 JunB 蛋白的蛋白酶体降解，负向控制 BM-MPC 的成骨细胞分化。瘙痒是骨合成代谢药物开发的潜在新靶点，用于治疗骨质流失患者。
Itch, a HECT family E3 ligase, affects numerous cell functions by regulating ubiquitination and proteasomal degradation of target proteins. However, the role of Itch in osteoblasts has not been investigated. We report that Itch−/− mice have significantly increased bone volume, osteoblast numbers and bone formation rate. Using bone marrow stromal cells from Itch−/− mice and WT littermates as bone marrow mesenchymal precursor cells (BM-MPCs), we found BM-MPCs from Itch−/− mice have compatible numbers of cells expressing mesenchymal stem cell markers. However, Itch−/− BM-MPCs grew faster in an in vitro culture, formed more CFU-F mesenchymal colonies, and exhibited increased osteoblast differentiation and decreased adipogenesis. Importantly, Itch−/− mesenchymal colony cells formed significantly more new bone in a tibial defect of recipient mice compared with WT cells. The expression levels of JunB, an AP-1 transcription factor that positively regulate osteoblast differentiation, were significantly increased in Itch−/− BM-MPCs when proteasome function is intact. In contrast, the amount of ubiquitinated JunB protein was markedly decreased in Itch−/− cells when proteasome function was blocked. Over-expression of WT Itch, but not an Itch ligase-inactive mutant, rescued differentiation defects of Itch−/− BM-MPCs. Itch−/− BM-MPCs had a similar role in immune modulation as WT cells. Thus, Itch negatively controls osteoblast differentiation from BM-MPCs through the regulation of proteasomal degradation of positive osteoblast regulator JunB protein. Itch is a potential new target for bone anabolic drug development to treat patients with bone loss.
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影响因子：
5.2
作者：
Zhao, Lan;Huang, Jian;Zhang, Hengwei;Wang, Yi;Matesic, Lydia E.;Takahata, Masahiko;Awad, Hani;Chen, Di;Xing, Lianping
通讯作者：
Xing, Lianping
小鼠致密骨间充质干细胞分离和培养方案
影响因子：
14.8
作者：
Zhu, Heng;Guo, Zi-Kuan;Mao, Ning
通讯作者：
Mao, Ning
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
64.5
作者：
Yamashita, M;Ying, SX;Zhang, YE
通讯作者：
Zhang, YE
影响因子：
2.6
作者：
Bartholomew, A;Sturgeon, C;Hoffman, R
通讯作者：
Hoffman, R