CXCL12-CXCR4/7信号轴调控钛种植体周围的异物反应

doi:10.13701/j.cnki.kqyxyj.2025.03.010

摘要/Abstract

摘要： 目的: 探究趋化因子12(C-X-C motif ligand 12,CXCL12)-趋化因子受体4/7(C-X-C chemokine receptor type 4/7, CXCR4/7)信号轴在钛种植体周围的异物反应过程中的调控作用。方法: 利用流式细胞术检测聚甲基丙烯酸甲酯(poly methyl methacrylate,PMMA)和钛(titanium, Ti)两种材料对巨噬细胞CXCR4、CXCR7表达情况的影响,实时荧光定量逆转录聚合酶链反应(quantitative reverse transcription-polymerase chain reaction,qRT-PCR)和流式细胞术检测巨噬细胞分型及相关炎性细胞因子的表达情况。构建植入体异物反应动物模型。实验动物分为4组:植入Ti种植体组、植入Ti种植体组并注射AMD3100、植入PMMA种植体组和植入PMMA种植体并注射辛伐他汀(simvastatin, Sim)。免疫组织化学检测、免疫荧光和苏木精-伊红(hematoxylin-eosin, HE)染色检测种植体周围CXCL12-CXCR4/CXCR7通路的表达情况、巨噬细胞功能状况以及异物反应情况。结果: 体外实验结果显示,Ti促进巨噬细胞CXCR4表达上升、CXCR7表达下降且巨噬细胞向抗炎型转化。体内实验结果显示,Ti植入物附近CXCR4高表达,CXCR7低表达,PMMA组则相反。并且Ti组的抗炎M2型巨噬细胞数量在所有时间点都明显高于PMMA组,HE染色结果表明Ti组异物反应较轻。当分别加入CXCR4拮抗剂或CXCR7拮抗剂后,Ti和PMMA种植体周围情况逆转。结论: CXCL12-CXCR4/7信号轴可以成为调控Ti种植体周围异物反应的新靶点。

关键词: 异物反应, 巨噬细胞, CXCR4, CXCR7

Abstract: Objective: To investigate the regulatory role of C-X-C motif ligand 12 (CXCL12)-C-X-C chemokine receptor type 4/7 (CXCR4/7) axis in the foreign body response (FBR) around titanium implants. Methods: The effects of polymethyl methacrylate (PMMA) and titanium (Ti) on the expression of CXCR4 and CXCR7 of macrophages were detected by flow cytometry. Besides, macrophage typing and the expression of related inflammatory cytokines were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and flow cytometry. Animal models of implant foreign body reaction were constructed. The experimental animals were divided into four groups: the titanium implant group, the titanium implant group injected with AMD3100, the PMMA implant group, and the PMMA implant with simvastatin (Sim) injection. Then, the expression of CXCL12-CXCR4/CXCR7 pathway, the function of macrophages, and the foreign body reaction around the implant were detected by immunohistochemical staining, immunofluorescence staining, and HE staining. Results: In vitro experiments showed that titanium promoted the increase of CXCR4 expression and the decrease of CXCR7 expression on macrophages, and the transformation of macrophages into anti-inflammatory types. Immunohistochemical staining showed that CXCR4 was highly expressed and CXCR7 was low around Ti implant, while the PMMA group was opposite. Immunofluorescence staining of macrophages showed that the number of anti-inflammatory M2 macrophages in the titanium group was significantly higher than that in the PMMA group at all time points, and HE staining showed that the FBR in the titanium group was mild. When CXCR4 antagonists or CXCR7 antagonists were added, respectively, the peri-implant conditions of titanium and PMMA implants were reversed. Conclusion: The CXCRL12-CXCR4/7 axis can be a new target for regulating the FBR around titanium implants.

Key words: foreign body response, macrophage, CXCR4, CXCR7

余思懿, 蔡新杰, 黄翠. CXCL12-CXCR4/7信号轴调控钛种植体周围的异物反应[J]. 口腔医学研究, 2025, 41(3): 229-237.

YU Siyi, CAI Xinjie, HUANG Cui. CXCL12-CXCR4/CXCR7 Axis Modulates Foreign Body Response around Titanium Implant[J]. Journal of Oral Science Research, 2025, 41(3): 229-237.

参考文献

[1] Niinomi M. Mechanical biocompatibilities of titanium alloys for biomedical applications[J].J Mech Behav Biomed Mater, 2008, 1(1): 30-42.
[2] Elani HW, Starr JR, Da Silva JD, et al. Trends in dental implant use in the U.S., 1999-2016, and projections to 2026[J].J Dent Res, 2018, 97(13): 1424-1430.
[3] de Avila ED, van Oirschot BA, van den Beucken J. Biomaterial-based possibilities for managing peri-implantitis[J].J Periodontal Res, 2020, 55(2): 165-173.
[4] Guglielmotti MB, Olmedo DG, Cabrini RL. Research on implants and osseointegration[J].Periodontol 2000, 2019, 79(1): 178-189.
[5] Schwarz F, Ramanauskaite A. It is all about peri-implant tissue health[J].Periodontol 2000, 2022, 88(1): 9-12.
[6] 林国芬,许杨波,王思源,等.种植失败原因分析[J].口腔医学,2023,43(1): 18-23.
[7] Bielemann AM, Marcello-Machado RM, Leite FRM, et al. Comparison between inflammation-related markers in peri-implant crevicular fluid and clinical parameters during osseointegration in edentulous jaws[J].Clin Oral Investig, 2018, 22(1): 531-543.
[8] Jemat A, Ghazali MJ, Razali M, et al. Surface modifications and their effects on titanium dental implants[J].Biomed Res Int, 2015: 791725.
[9] Smeets R, Stadlinger B, Schwarz F, et al. Impact of dental implant surface modifications on osseointegration[J].Biomed Res Int, 2016: 6285620.
[10] Podzimek S, Tomka M, Nemeth T, et al. Influence of metals on cytokines production in connection with successful implantation therapy in dentistry[J].Neuro Endocrinol Lett, 2010, 31(5): 657-662.
[11] Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials[J].Semin Immunol, 2008, 20(2): 86-100.
[12] Niu Y, Wang Z, Shi Y, et al. Modulating macrophage activities to promote endogenous bone regeneration: Biological mechanisms and engineering approaches[J].Bioact Mater, 2021, 6(1): 244-261.
[13] 严佳慧,郎欣蕊,章燕珍.巨噬细胞在种植体骨结合及早期失败的研究进展[J].口腔颌面修复学杂志,2022,23(1): 70-74.
[14] Doitsidou M, Reichman-Fried M, Stebler J, et al. Guidance of primordial germ cell migration by the chemokine SDF-1[J].Cell, 2002, 111(5): 647-659.
[15] Song M, Jang H, Lee J, et al. Regeneration of chronic myocardial infarction by injectable hydrogels containing stem cell homing factor SDF-1 and angiogenic peptide Ac-SDKP[J].Biomaterials, 2014, 35(8): 2436-2445.
[16] Petruzziello-Pellegrini TN, Yuen DA, Page AV, et al. The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin-associated hemolytic uremic syndrome in humans and mice[J].J Clin Invest, 2012, 122(2): 759-776.
[17] Kyriakides TR, Kim HJ, Zheng C, et al. Foreign body response to synthetic polymer biomaterials and the role of adaptive immunity[J].Biomed Mater, 2022, 17(2):10.1088/1748-605X/ac5574.
[18] Cai X, Chen R, Ma K, et al. Identification of the CXCL12-CXCR4/CXCR7 axis as a potential therapeutic target for immunomodulating macrophage polarization and foreign body response to implanted biomaterials[J].Applied Materials Today, 2020, 18: 100454.
[19] Insua A, Monje A, Wang HL, et al. Basis of bone metabolism around dental implants during osseointegration and peri-implant bone loss[J].J Biomed Mater Res A, 2017, 105(7): 2075-2089.
[20] Roccuzzo A, Imber JC, Salvi GE, et al. Peri-implantitis as the consequence of errors in implant therapy[J].Periodontol 2000, 2023, 92(1): 350-361.
[21] Trindade R, Albrektsson T, Tengvall P, et al. Foreign body reaction to biomaterials: On mechanisms for buildup and breakdown of osseointegration[J].Clin Implant Dent Relat Res, 2016, 18(1): 192-203.
[22] Abaricia JO, Shah AH, Ruzga MN, et al. Surface characteristics on commercial dental implants differentially activate macrophages in vitro and in vivo[J].Clin Oral Implants Res, 2021, 32(4): 487-497.
[23] Yang Y, Zhang T, Jiang M, et al. Effect of the immune responses induced by implants in a integrated three-dimensional micro-nano topography on osseointegration[J].J Biomed Mater Res A, 32021, 109(8): 1429-1440.
[24] Mesa-Restrepo A, Byers E, Brown JL, et al. Osteointegration of Ti bone implants: A study on how surface parameters control the foreign body response[J].ACS Biomater Sci Eng, 2024, 10(8): 4662-4681.
[25] Yang N, Wu T, Li M, et al. Silver-quercetin-loaded honeycomb-like Ti-based interface combats infection-triggered excessive inflammation via specific bactericidal and macrophage reprogramming[J].Bioact Mater, 2025, 43: 48-66.
[26] Thevenot PT, Nair AM, Shen J, et al. The effect of incorporation of SDF-1alpha into PLGA scaffolds on stem cell recruitment and the inflammatory response[J].Biomaterials, 2010, 31(14): 3997-4008.
[27] Haider H, Jiang S, Idris NM, et al. IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair[J].Circ Res, 2008, 103(11): 1300-1308.
[28] O'Neill LA. Targeting signal transduction as a strategy to treat inflammatory diseases[J].Nat Rev Drug Discov, 2006, 5(7): 549-563.
[29] Furlong M, Seong JY. Evolutionary and comparative genomics to drive rational drug design, with particular focus on neuropeptide seven-transmembrane receptors[J].Biomol Ther (Seoul), 2017, 25(1): 57-68.
[30] Correll CC, McKittrick BA. Biased ligand modulation of seven transmembrane receptors (7TMRs): functional implications for drug discovery[J].J Med Chem, 2014, 57(16): 6887-6896.
[31] Ahmad R, Wojciech S, Jockers R. Hunting for the function of orphan GPCRs- beyond the search for the endogenous ligand[J].Br J Pharmacol, 2015, 172(13): 3212-3228.
[32] Rask-Andersen M, Almén MS, Schiöth HB. Trends in the exploitation of novel drug targets[J].Nat Rev Drug Discov, 2011, 10(8): 579-590.

编辑推荐 0

Metrics

阅读次数

全文

HTML			PDF

最新录用	在线预览	正式出版	最新录用	在线预览	正式出版
0	0	0	0	0	4

	来源	本网站

	次数	4
	比例	100%

摘要

最新录用	在线预览	正式出版

0	0	30

	来源	本网站

	次数	30
	比例	100%