Sustained calcium ion release from bioceramics promotes CaSR-mediated M2 macrophage polarization for osteoinduction,Journal of Leukocyte Biology

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Sustained calcium ion release from bioceramics promotes CaSR-mediated M2 macrophage polarization for osteoinduction
Journal of Leukocyte Biology ( IF 3.6 ) Pub Date : 2021-06-28 , DOI: 10.1002/jlb.3ma0321-739r
Jinglun Zhang ₁ , Qian Wu ₂ , Chengcheng Yin ₁ , Xiaoshi Jia ₁ , Zifan Zhao ₁ , Xiaoxin Zhang _{1,

3} , Guohua Yuan ₁ , Hao Hu ₄ , Qin Zhao ₁

Affiliation

Innate immune cells, especially macrophages, play a dual role in tissue repair and the defense against foreign bodies. Although biphasic calcium phosphate (BCP) ceramics have been confirmed as an excellent osteoimmunoregulatory biomaterial, it is unclear whether the ions release of BCP directly affects macrophage polarization and the mechanism by which the ions release is involved in osteoimmunomodulation. Herein, we verified the superior osteoinductive capacity of BCP in wild-type mice and showed its inability to promote this process in macrophage-deficient (LysM^−/−) mice. Moreover, scanning electron microscopy, ion release curve, and calcein AM-staining results confirmed that BCP-released Ca²⁺ in a sustained manner, thereby maintaining the long-term induction of M2 macrophage polarization and promoting the differentiation of mesenchymal stem cells into osteoblasts during osteogenesis. Furthermore, Ca²⁺ targeted the Wnt/β-catenin signaling pathway and activated Arg1 and IL-10 (M2 marker genes) transcription through the calcium-sensing receptor (CaSR) in macrophages. Under treatment with a CaSR antagonist, macrophages cultured with the BCP fluid extract exhibited lower Ca²⁺ intake and weaker M2 macrophage polarization. These findings underscore the critical role of macrophages in bone regeneration and clarify the molecular mechanisms of Ca²⁺-mediated osteoinduction by biomaterials, which is of great significance for the future design of biomaterial-oriented tissue regeneration engineering.

中文翻译：

从生物陶瓷中持续释放钙离子促进 CaSR 介导的 M2 巨噬细胞极化用于骨诱导

先天免疫细胞，尤其是巨噬细胞，在组织修复和异物防御中发挥双重作用。虽然双相磷酸钙（BCP）陶瓷已被证实是一种优良的骨免疫调节生物材料，但尚不清楚 BCP 的离子释放是否直接影响巨噬细胞极化以及离子释放参与骨免疫调节的机制。在此，我们验证了 BCP 在野生型小鼠中的卓越骨诱导能力，并显示其无法在巨噬细胞缺陷 ( LysM ^-/- ) 小鼠中促进这一过程。此外，扫描电子显微镜、离子释放曲线和钙黄绿素 AM 染色结果证实 BCP 释放的 Ca ²⁺以持续的方式，从而维持M2巨噬细胞极化的长期诱导，并促进间充质干细胞在成骨过程中分化为成骨细胞。此外，Ca ²⁺靶向 Wnt/β-catenin 信号通路并通过巨噬细胞中的钙敏感受体 (CaSR)激活Arg1和IL-10 （M2 标记基因）转录。在用 CaSR 拮抗剂处理时，用 BCP 液提取物培养的巨噬细胞表现出较低的 Ca ²⁺摄入量和较弱的 M2 巨噬细胞极化。这些发现强调了巨噬细胞在骨再生中的关键作用，并阐明了 Ca ^{2+的分子机制}介导的生物材料成骨诱导作用，这对于未来设计以生物材料为导向的组织再生工程具有重要意义。

更新日期：2021-08-27

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