Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
Department of Orofacial Sciences, School of Dentistry, University of California, San Francisco (UCSF), San Francisco, CA, USA.
Stem Cells. 2022 Sep 26;40(9):818-830. doi: 10.1093/stmcls/sxac042.
Nerve growth factor (NGF) is the best-characterized neurotrophin and is primarily recognized for its key role in the embryonic development of the nervous system and neuronal cell survival/differentiation. Recently, unexpected actions of NGF in bone regeneration have emerged as NGF is able to enhance the osteogenic differentiation of mesenchymal stem cells. However, little is known regarding how NGF signaling regulates osteogenic differentiation through epigenetic mechanisms. In this study, using human dental mesenchymal stem cells (DMSCs), we demonstrated that NGF mediates osteogenic differentiation through p75NTR, a low-affinity NGF receptor. P75NTR-mediated NGF signaling activates the JNK cascade and the expression of KDM4B, an activating histone demethylase, by removing repressive H3K9me3 epigenetic marks. Mechanistically, NGF-activated c-Jun binds to the KDM4B promoter region and directly upregulates KDM4B expression. Subsequently, KDM4B directly and epigenetically activates DLX5, a master osteogenic gene, by demethylating H3K9me3 marks. Furthermore, we revealed that KDM4B and c-Jun from the JNK signaling pathway work in concert to regulate NGF-mediated osteogenic differentiation through simultaneous recruitment to the promoter region of DLX5. We identified KDM4B as a key epigenetic regulator during the NGF-mediated osteogenesis both in vitro and in vivo using the calvarial defect regeneration mouse model. In conclusion, our study thoroughly elucidated the molecular and epigenetic mechanisms during NGF-mediated osteogenesis.
神经生长因子（NGF）是研究最为透彻的神经营养因子，其主要功能是在神经系统胚胎发育和神经元存活/分化中发挥关键作用。最近，NGF 在骨再生中的意外作用逐渐显现，因为 NGF 能够增强间充质干细胞的成骨分化。然而，关于 NGF 信号如何通过表观遗传机制调节成骨分化，人们知之甚少。在这项研究中，我们使用人牙髓间充质干细胞（DMSCs）证明，NGF 通过低亲和力 NGF 受体 p75NTR 介导成骨分化。p75NTR 介导的 NGF 信号通过去除抑制性 H3K9me3 表观遗传标记来激活 JNK 级联和激活组蛋白去甲基酶 KDM4B 的表达。在机制上，NGF 激活的 c-Jun 结合到 KDM4B 启动子区域，直接上调 KDM4B 的表达。随后，KDM4B 通过去甲基化 H3K9me3 标记，直接和表观遗传激活主成骨基因 DLX5。此外，我们揭示了 JNK 信号通路中的 KDM4B 和 c-Jun 通过同时募集到 DLX5 的启动子区域，协同作用调节 NGF 介导的成骨分化。我们使用颅骨缺损再生小鼠模型，在体内和体外实验中均证实 KDM4B 是 NGF 介导的成骨作用中的关键表观遗传调控因子。总之，我们的研究彻底阐明了 NGF 介导的成骨作用中的分子和表观遗传机制。
