Signaling pathways involved in the effects of HMGB1 on mesenchymal stem cell migration and osteoblastic differentiation
Signaling pathways involved in the effects of HMGB1 on mesenchymal stem cell migration and osteoblastic differentiation
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HMGB1影响间充质干细胞迁移和成骨细胞分化的信号通路
DOI：
10.3892/ijmm.2016.2479
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发表时间：
2016-03-01
影响因子：
5.4
通讯作者：
Pan, Zhijun
中科院分区：
文献类型：
--
作者：
Lin, Feng;Zhang, Wei;Pan, Zhijun
高迁移率族蛋白1（HMGB 1）在骨折炎症微环境中表达。众所周知，HMGB 1作为间充质干细胞（MSC）的化学引诱剂;然而，HMGB 1对MSC迁移和成骨细胞分化的影响，以及参与这些影响的信号通路，尚未阐明。在这项研究中，我们的目的是研究这些影响，以及所涉及的信号转导机制，使用体外模型。我们发现不同浓度的HMGB 1可促进MSCs向成骨细胞分化，促进晚期糖基化终产物受体（Receptor for Advanced Glycation End Products，ERK）和Toll样受体（Toll-like receptor，TLR）2/4的合成，并激活p38丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）和核因子-κ B（nuclear factor-kappa B）信号通路。随后，我们在适当浓度的HMGB 1中培养MSC，并使用受体中和抗体和信号通路抑制剂来确定HMGB 1对MSC迁移和分化的影响所涉及的信号通路。从本研究的结果中，我们得出结论，HMGB 1通过激活p38 MAPK信号通路促进MSC迁移，并且还通过结合TLR 2/4并激活p38 MAPK信号通路促进MSC分化。这些发现阐明了HMGB 1在骨折微环境中作用的机制，这可能为开发改进的骨折临床治疗方法提供理论基础。
High mobility group box 1 (HMGB1) epxression has been found in the inflammatory microenvironment of fractures. It is well known that HMGB1 acts as a chemoattractant for mesenchymal stem cells (MSCs); however, the effects of HMGB1 on MSC migration and osteoblastic differentiation, and the signaling pathways involved in these effects, have not yet been elucidated. In this study, we aimed to investigate these effects, as well as the signaling mechanisms involved, using in vitro models. We found that HMGB1, in varying concentrations, promoted the osteoblastic differentiation of MSCs, the synthesis of receptor for advanced glycation end products (RAGE) and Toll-like receptor (TLR)2/4, and the activation of the p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappa B) signaling pathways. Subsequently, we cultured the MSCs in the appropriate concentration of HMGB1, and determined the signaling pathways involved in the effects of HMGB1 on MSC migration and differentiation, using receptor neutralizing antibodies and signaling pathway inhibitors. From the results of this study, we concluded that HMGB1 promotes MSC migration through the activation of the p38 MAPK signaling pathway, and also promotes MSC differentiation by binding to TLR2/4 and activating the p38 MAPK signaling pathway. These findings elucidate the mechanisms underlying the effects of HMGB1 in the fracture microenvironment, which may provide a theoretical basis for the development of improved clinical treatments for fractures.