Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK
Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK
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DOI：
10.1074/jbc.m702391200
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发表时间：
2007-10-19
影响因子：
4.8
通讯作者：
Wang, Cun-Yu
中科院分区：
文献类型：
--
作者：
Chang, Jia;Sonoyama, Wataru;Wang, Cun-Yu
间充质干细胞（MSC）是多能细胞，可以分化为成骨细胞，为骨再生和修复提供优良的细胞来源。最近，人们发现经典的 Wnt/β-catenin 信号通路在骨骼发育和成骨中发挥着关键作用，这意味着 Wnt 可用于改善 MSC 介导的从头骨形成。然而，非经典 Wnt 信号传导是否调节成骨分化尚不清楚。在这里，我们发现 Wnt-4 增强了从人类成人颅面组织中分离的 MSC 的体外成骨分化，并促进体内骨形成。虽然 Wnt-4 不能稳定 β-连环蛋白，但它可以在一种新型非经典信号通路中激活 p38 MAPK。 p38 的激活依赖于 Axin，并且是 Wnt-4 增强 MSC 分化所必需的。此外，使用两种不同的颅面骨损伤模型，我们发现通过基因工程改造表达Wnt-4的间充质干细胞增强了成骨作用并改善了颅面缺损的体内修复。综上所述，我们的结果表明非经典 Wnt 信号传导也可能在成骨分化中发挥作用。 Wnt-4 可能在改善骨再生和修复颅面缺损方面具有潜在用途。
Mesenchymal stem cells (MSCs) are multipotent cells that can be differentiated into osteoblasts and provide an excellent cell source for bone regeneration and repair. Recently, the canonical Wnt/beta-catenin signaling pathway has been found to play a critical role in skeletal development and osteogenesis, implying that Wnts can be utilized to improve de novo bone formation mediated by MSCs. However, it is unknown whether noncanonical Wnt signaling regulates osteogenic differentiation. Here, we find that Wnt-4 enhanced in vitro osteogenic differentiation of MSCs isolated from human adult craniofacial tissues and promoted bone formation in vivo. Whereas Wnt-4 did not stabilize beta-catenin, it activated p38 MAPK in a novel noncanonical signaling pathway. The activation of p38 was dependent on Axin and was required for the enhancement of MSC differentiation by Wnt-4. Moreover, using two different models of craniofacial bone injury, we found that MSCs genetically engineered to express Wnt-4 enhanced osteogenesis and improved the repair of craniofacial defects in vivo. Taken together, our results reveal that noncanonical Wnt signaling could also play a role in osteogenic differentiation. Wnt-4 may have a potential use in improving bone regeneration and repair of craniofacial defects.