Wang Jing, Liu Dan, Guo Bo, Yang Xiao, Chen Xuening, Zhu Xiangdong, Fan Yujiang, Zhang Xingdong
National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China.
Acta Biomater. 2017 Mar 15;51:447-460. doi: 10.1016/j.actbio.2017.01.059. Epub 2017 Jan 23.
The inflammatory reaction initiates fracture healing and could play a role in the osteoinductive effect of calcium phosphate (CaP) ceramics, which has been widely confirmed; however, the underlying mechanism has not been fully elucidated. In this study, various signaling molecules from macrophages under the stimulation of osteoinductive biphasic calcium phosphate (BCP) ceramic and its degradation products were examined and evaluated for their influence on the migration and osteoblastic differentiation of mesenchymal stem cells (MSCs). The results of cellular experiments confirmed that the gene expression of most inflammatory factors (IL-1, IL-6 and MCP-1) and growth factors (VEGF, PDGF and EGF) by macrophages were up-regulated to varying degrees by BCP ceramic and its degradation products. Cell migration tests demonstrated that the conditioned media (CMs), which contained abundant signaling molecules secreted by macrophages cultured on BCP ceramic and its degradation products, promoted the migration of MSCs. qRT-PCR analysis indicated that CMs promoted the gene expression of osteogenic markers (ALP, COL-I, OSX, BSP and OPN) in MSCs. ALP activity and mineralization staining further confirmed that CMs promoted the osteoblastic differentiation of MSCs. The present study confirmed the correlation between the inflammatory reaction and osteoinductive capacity of BCP ceramic. The ceramic itself and its degradation products can induce macrophages to express and secrete various signaling molecules, which then recruit and promote the MSCs to differentiate into osteoblasts. Compared with BCP conditioned media, degradation particles played a more substantial role in this process. Thus, inflammation initiated by BCP ceramic and its degradation products could be necessary for osteoinduction by the ceramic.
It is known that the inflammatory reaction initiates fracture healing. The aim of this study was to examine whether osteoinductive BCP ceramics could cause macrophages to change their secretion patterns and whether the secreted cytokines could affect migration and osteoblastic differentiation of MSCs. Moreover, the duration of inflammation could be influenced by the local ionic environment and the degradation products of the implant. Our experimental results revealed the correlation between the inflammatory reaction and osteoinductive capacity of BCP ceramic. The ceramic itself and its degradation products can induce macrophages to express and secrete various signaling molecules, which then recruit and promote the MSCs to differentiate into osteoblasts. Compared with ionic microenvironment, degradation particles played a more substantial role in this process. Therefore, the appropriate inflammation initiated by BCP ceramic and its degradation products could be essential for osteoinduction by the ceramic. We believe that the present study improves the understanding of the effect of biomaterial-mediated inflammation on MSC migration and differentiation and established a preliminary correlation between the immune system and osteoinduction by biomaterials.
炎症反应启动骨折愈合，并可能在磷酸钙（CaP）陶瓷的骨诱导作用中发挥作用，这一点已得到广泛证实；然而，其潜在机制尚未完全阐明。在本研究中，检测并评估了在骨诱导性双相磷酸钙（BCP）陶瓷及其降解产物刺激下巨噬细胞产生的各种信号分子对间充质干细胞（MSC）迁移和成骨分化的影响。细胞实验结果证实，BCP陶瓷及其降解产物不同程度地上调了巨噬细胞中大多数炎症因子（IL-1、IL-6和MCP-1）和生长因子（VEGF、PDGF和EGF）的基因表达。细胞迁移试验表明，含有在BCP陶瓷及其降解产物上培养的巨噬细胞分泌的丰富信号分子的条件培养基（CMs）促进了MSC的迁移。qRT-PCR分析表明，CMs促进了MSC中成骨标志物（ALP、COL-I、OSX、BSP和OPN）的基因表达。ALP活性和矿化染色进一步证实，CMs促进了MSC的成骨分化。本研究证实了BCP陶瓷的炎症反应与骨诱导能力之间的相关性。陶瓷本身及其降解产物可诱导巨噬细胞表达和分泌各种信号分子，进而募集并促进MSC分化为成骨细胞。与BCP条件培养基相比，降解颗粒在这一过程中发挥了更重要的作用。因此，BCP陶瓷及其降解产物引发的炎症可能是陶瓷骨诱导所必需的。
众所周知，炎症反应启动骨折愈合。本研究的目的是检验骨诱导性BCP陶瓷是否能使巨噬细胞改变其分泌模式，以及分泌的细胞因子是否会影响MSC的迁移和成骨分化。此外，炎症持续时间可能受局部离子环境和植入物降解产物的影响。我们的实验结果揭示了BCP陶瓷的炎症反应与骨诱导能力之间的相关性。陶瓷本身及其降解产物可诱导巨噬细胞表达和分泌各种信号分子，进而募集并促进MSC分化为成骨细胞。与离子微环境相比，降解颗粒在这一过程中发挥了更重要的作用。因此，BCP陶瓷及其降解产物引发的适当炎症可能是陶瓷骨诱导所必需的。我们相信，本研究增进了对生物材料介导的炎症对MSC迁移和分化影响的理解，并建立了免疫系统与生物材料骨诱导之间的初步相关性。
