Cytokine Mixtures Mimicking Secretomes From Mesenchymal Stem Cells Improve Medication-Related Osteonecrosis of the Jaw in a Rat Model.
Cytokine Mixtures Mimicking Secretomes From Mesenchymal Stem Cells Improve Medication-Related Osteonecrosis of the Jaw in a Rat Model.
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DOI：
10.1002/jbm4.10013
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发表时间：
2018-03
期刊：
影响因子：
3.8
通讯作者：
Nakamura S
中科院分区：
文献类型：
--
作者：
Ogata K;Matsumura M;Moriyama M;Katagiri W;Hibi H;Nakamura S
最近，几项研究表明，静脉注射间充质干细胞（MSC）可改善药物相关性颌骨骨坏死（MRONJ），并且MSC分泌组的旁分泌效应被假设为主要贡献者。来自人MSC（MSC-CM）的条件培养基中的这些分泌物组先前被证明促进骨和组织再生。由于MSC-CM含有细胞因子单核细胞趋化蛋白（MCP）-1、胰岛素生长因子（IGF）-1和血管内皮生长因子（VEGF），其浓度相对高于其他因子，因此认为这些细胞因子是组织再生的相关活性因子。通过将MCP-1、IGF-1和VEGF的重组蛋白以相同浓度混合在MSC-CM中，我们制备了模拟MSC-CM的细胞因子混合物，然后在大鼠MRONJ模型中评估其治疗效果。在体外，细胞因子混合物促进大鼠骨髓间充质干细胞的成骨分化，迁移和增殖。此外，这些维持了骨质疏松功能。在体内，我们使用大鼠MRONJ模型来检查通过静脉内施用的细胞因子混合物的治疗效果。在MSC-CM或细胞因子混合物组中，分别有66%或67%的MRONJ大鼠的开放性牙槽窝愈合，软组织完全覆盖和牙槽骨，而在其他组中，暴露的坏死骨和发炎的软组织仍然存在。组织学分析显示，在MSC‐CM或细胞因子混合物组中新骨形成和破骨细胞的出现;然而，在其他组中破骨细胞显著减少。因此，我们得出结论，静脉注射细胞因子混合物可能是治疗MRONJ患者的有效治疗方式。© 2017 The Authors JBMR Plus由Wiley Periodicals，Inc.出版。美国骨与矿物质研究协会（American Society for Bone and Mineral Research）
Recently, several studies have demonstrated that intravenous administration of mesenchymal stem cells (MSCs) improve medication‐related osteonecrosis of the jaw (MRONJ), and paracrine effects of secretomes from MSCs have been hypothesized as the primary contributors. These secretomes in conditioned media from human MSCs (MSC‐CM) were previously demonstrated to promote bone and tissue regeneration. Because MSC‐CM contain cytokines monocyte chemoattractant protein (MCP)‐1, insulin growth factor (IGF)‐1, and vascular endothelial growth factor (VEGF) at relatively higher concentrations than other factors, these cytokines were considered as relevant active factors for tissue regeneration. By mixing the recombinant proteins of MCP‐1, IGF‐1, and VEGF, included at the same concentrations in MSC‐CM, we prepared cytokine mixtures mimicking MSC‐CM and then evaluated its therapeutic effects in a rat MRONJ model. In vitro, cytokine mixtures promoted osteogenic differentiation, migration, and proliferation of rat MSCs. In addition, these maintained osteoclastic function. In vivo, we used a rat MRONJ model to examine therapeutic effects of the cytokine mixtures through intravenous administration. In MSC‐CM or cytokine mixture group, open alveolar sockets in 66% or 67% of the rats with MRONJ, respectively, healed with complete soft tissue coverage and socket bones, whereas in the other groups, the exposed necrotic bone with inflamed soft tissue remained. Histological analysis revealed new bone formation and the appearance of osteoclasts in MSC‐CM or cytokine mixture group; however, osteoclasts were significantly reduced in the other groups. Thus, we concluded that intravenous administration of cytokine mixtures might be an effective therapeutic modality for treating patients with MRONJ. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research