微小RNA-146a调节骨代谢在骨组织工程中的应用

doi:10.12307/2026.752

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (18): 4702-4712.doi: 10.12307/2026.752

• 组织构建综述 tissue construction review • 上一篇

微小RNA-146a调节骨代谢在骨组织工程中的应用

李佳音，隋磊，李彦静

天津医科大学口腔医(学)院/天津医科大学，天津市 300070

收稿日期:2025-09-03 接受日期:2025-09-26 出版日期:2026-06-28 发布日期:2025-12-08
通讯作者: 李彦静，博士，副研究员，天津医科大学口腔医(学)院/天津医科大学，天津市 300070
作者简介:李佳音，女，1999年生，安徽省临泉县人，汉族，2024年天津医科大学毕业，硕士，主要从事口腔修复学方面的研究。
基金资助:
国家自然科学基金青年科学基金项目(C类)(82301030)，项目负责人：李彦静；天津市自然科学基金青年项目
(23JCQNJC00440)，项目负责人：李彦静

microRNA-146a regulates bone metabolism and its application in bone tissue engineering

Li Jiayin, Sui Lei, Li Yanjing

Tianjin Medical University School of Stomatology/Tianjin Medical University, Tianjin 300070, China

Received:2025-09-03 Accepted:2025-09-26 Online:2026-06-28 Published:2025-12-08
Contact: Li Yanjing, MD, Associate researcher, Tianjin Medical University School of Stomatology/Tianjin Medical University, Tianjin 300070, China
About author:Li Jiayin, MS, Tianjin Medical University School of Stomatology/Tianjin Medical University, Tianjin 300070, China
Supported by:
National Natural Science Foundation of China (Young Scientists Fund; Category C), No. 82301030 (to LYJ); Natural Science Foundation of Tianjin (Young Program), No. 23JCQNJC00440 (to LYJ)

摘要/Abstract

摘要：

文题释义：
微小RNA-146a：微小RNA(microRNA，miRNA)是一类由21-23个核苷酸构成的内源性非编码单链RNA，其能与mRNA的3’非编码区域(3’URT)完全配对诱导目标mRNA的直接降解，或不完全配对抑制mRNA的翻译，从而抑制蛋白质的合成，实现基因沉默。其中miR-146a在人体内由5号染色体上的LOC285628基因编码，可在多种组织细胞中表达，参与调控机体代谢、组织发育、炎症刺激的免疫反应等生物学过程。
miR-146a在骨代谢相关疾病的发展过程中变化显著，miR-146a可能作为骨代谢疾病诊疗的潜在靶点。
骨代谢：是骨细胞间以及骨细胞与基质细胞间通过相互作用进行骨改建和重建。稳定的骨代谢能形成并维持具有正常结构和功能的骨组织，骨代谢异常则是骨质疏松、骨关节炎、牙周炎等骨代谢疾病的主要发病机制。骨代谢过程的关键细胞成骨细胞、破骨细胞生物学行为异常，或组织周围炎症微环境均会造成骨代谢过程失衡，引发骨代谢相关疾病。

背景：正常骨代谢有赖于成骨细胞介导的骨形成与破骨细胞介导的骨吸收之间的平衡，破坏该平衡会引发骨代谢相关疾病。微小RNA-146a (miR-146a)是一种非编码小分子RNA，在骨代谢中发挥重要作用。
目的：就微小RNA-146a调控骨代谢的分子机制及其在骨组织工程中的应用做一综述。
方法：作者于2025年4月对中国知网、PubMed和Web of Science数据库中2000年1月至2025年4月发表的相关文献进行检索，中文检索词为“微小RNA-146a，骨，骨代谢，成骨细胞，破骨细胞，骨组织再生”；英文检索词为“microRNA-146a，Bone metabolism，Osteoblast，Osteoclast，Bone regeneration”，检索文献类型不限。共检索到文献11 230篇，其中中国知网检索到中文文献988篇，PubMed数据库检索到英文文献5 952篇，Web of Science数据库检索到英文文献4 290篇。目标纳入研究骨代谢过程及其影响因素的相关文献，探究微小RNA-146a如何调控骨代谢过程、骨代谢关键细胞生物学行为的相关文献，微小RNA-146a应用于维持骨稳态、促进骨组织修复再生的相关文献；排除与文章主题相关度低、内容较陈旧、实验设计不严密、研究结果可信度较差、论证不充分的文献。最终根据文献排除标准筛选出与该综述主题密切相关且研究新颖、数据真实可信、论证充分、具有临床应用价值的90篇文献进行综述。
结果与结论：①微小RNA-146a可通过抑制Wnt、Smad4、沉默信息调节因子2相关酶1等基因表达抑制成骨细胞形成及活性，或通过抑制肿瘤坏死因子受体相关因子6、白细胞介素1受体相关激酶1基因表达抑制破骨细胞形成，也可调节成骨细胞与破骨细胞的相互作用；②微小RNA-146a的异常表达可使成骨细胞和破骨细胞功能失调，打破骨代谢平衡，引发骨质疏松、骨关节炎、牙周炎等骨代谢相关疾病；③因此，微小RNA-146a可作为骨代谢相关疾病诊疗的潜在靶点，在骨代谢相关疾病治疗和骨组织工程中具有一定的应用前景。

https://orcid.org/0009-0005-5018-3604(李佳音)

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: microRNA-146a, 骨代谢, 骨代谢疾病, 成骨细胞, 破骨细胞, 炎症, 骨组织再生, 骨组织工程

Abstract: BACKGROUND: Normal bone metabolism relies on the balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption. Disruption of this balance can lead to bone metabolism-related diseases. MicroRNA-146a is a non-coding small RNA molecule that plays a crucial role in bone metabolism.
OBJECTIVE: To review the molecular mechanisms by which microRNA-146a regulates bone metabolism and its applications in bone tissue engineering.
METHODS: In April 2025, the authors conducted a search of relevant literature published from January 2000 to April 2025 in the CNKI, PubMed, and Web of Science databases. The search terms used in Chinese included microRNA-146a, bone, bone metabolism, osteoblast, osteoclast, and bone tissue regeneration. The English search terms were microRNA-146a, bone metabolism, osteoblast, osteoclast, and bone regeneration. There is no restriction on the type of retrieved liter ature. A total of 11 230 documents were retrieved, comprising 988 Chinese documents from CNKI, 5 952 English documents from PubMed, and 4 290 English documents from Web of Science. The included literature focused on the process of bone metabolism and its influential factors, the regulation of bone metabolism by microRNA-146a, the biological behavior of key cells involved in bone metabolism, and the application of microRNA-146a in maintaining bone homeostasis and promoting bone tissue repair and regeneration. Literature with low relevance to the topic, outdated content, inadequate experimental design, poor credibility of research results, and insufficient argumentation were excluded. Based on the eligibility criteria, 90 articles closely related to the theme of this review—characterized by novel research, authentic and reliable data, sufficient argumentation, and clinical application value—were included in the final analysis.
RESULTS AND CONCLUSIONS: (1) MicroRNA-146a can inhibit the formation and activity of osteoblasts by suppressing the expression of genes such as Wnt, Smad4, and silencing information regulator 2-related enzyme 1. It can also inhibit the formation of osteoclasts by suppressing the expression of genes such as tumor necrosis factor receptor-associated factor 6 and interleukin-1 receptor-associated kinase 1. Additionally, it can regulate the interaction between osteoblasts and osteoclasts. (2) Abnormal expression of microRNA-146a can lead to dysfunction in osteoblasts and osteoclasts, disrupt the balance of bone metabolism, and induce osteoporosis, osteoarthritis, periodontitis, and other bone metabolism-related diseases. (3) MicroRNA-146a may serve as a potential target for the diagnosis and treatment of bone metabolism-related diseases, offering promising applications in the treatment of bone metabolism-related diseases and in bone tissue engineering.

Key words: microRNA-146a, bone metabolism, bone metabolism diseases, osteoblast, osteoclast, inflammation, bone tissue regeneration, bone tissue engineering

中图分类号:

李佳音, 隋磊, 李彦静. 微小RNA-146a调节骨代谢在骨组织工程中的应用[J]. 中国组织工程研究, 2026, 30(18): 4702-4712.

Li Jiayin, Sui Lei, Li Yanjing. microRNA-146a regulates bone metabolism and its application in bone tissue engineering[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(18): 4702-4712.

参考文献

[1] DIENER C, KELLER A, MEESE E. Emerging concepts of miRNA therapeutics: from cells to clinic. Trends Genet. 2022;38(6):613-626.
[2] LENG Q, CHEN L, LV Y. RNA-based scaffolds for bone regeneration: application and mechanisms of mRNA, miRNA and siRNA. Theranostics. 2020;10(7):3190-3205.
[3] PONZETTI M, RUCCI N. Osteoblast Differentiation and Signaling: Established Concepts and Emerging Topics. International Journal of Molecular Sciences. 2021;22(13): 6651.
[4] FRANCESCHI RT, GE C, XIAO G, et al. Transcriptional regulation of osteoblasts. Ann N Y Acad Sci. 2007;1116:196-207.
[5] SUN K, LUO J, GUO J, et al. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis Cartilage. 2020;28(4):400-409.
[6] KOOSHA E, EAMES BF. Two Modulators of Skeletal Development: BMPs and Proteoglycans. J Dev Biol. 2022;10(2):15.
[7] CUEVAS PL, AELLOS F, DAWID IM, et al. Wnt/β-Catenin Signaling in Craniomaxillofacial Osteocytes. Curr Osteoporos Rep. 2023; 21(2):228-240.
[8] CHEN G, DENG C, LI YP. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci. 2012;8(2):272-288.
[9] KOMORI T. Regulation of Skeletal Development and Maintenance by Runx2 and Sp7. Int J Mol Sci. 2024;25(18):10102.
[10] ZHU X, DU L, ZHANG L, et al. The critical role of toll-like receptor 4 in bone remodeling of osteoporosis: from inflammation recognition to immunity. Front Immunol. 2024;15:1333086.
[11] ONO T, HAYASHI M, SASAKI F, et al. RANKL biology: bone metabolism, the immune system, and beyond. Inflamm Regen. 2020; 40:2.
[12] MUN SH, PARK PSU, PARK-MIN KH. The M-CSF receptor in osteoclasts and beyond. Exp Mol Med. 2020;52(8):1239-1254.
[13] ZHANG C, LI H, LI J, et al. Oxidative stress: A common pathological state in a high-risk population for osteoporosis. Biomed Pharmacother. 2023;163:114834.
[14] JIANG T, XIA T, QIAO F, et al. Role and Regulation of Transcription Factors in Osteoclastogenesis. Int J Mol Sci. 2023; 24(22):16175.
[15] YAO Z, GETTING SJ, LOCKE IC. Regulation of TNF-Induced Osteoclast Differentiation. Cells. 2021;11(1):132.
[16] KITAURA H, MARAHLEH A, OHORI F, et al.Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption. Int J Mol Sci. 2020;21(14):5169.
[17] VEIS DJ, O’BRIEN CA. Osteoclasts, Master Sculptors of Bone. Annu Rev Pathol. 2023; 18:257-281.
[18] KEARNS AE, KHOSLA S, KOSTENUIK PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29(2):155-192.
[19] ROBLING AG, BONEWALD LF. The Osteocyte: New Insights. Annu Rev Physiol. 2020;82:485-506.
[20] DE LEON-OLIVA D, BARRENA-BLÁZQUEZ S, JIMÉNEZ-ÁLVAREZ L, et al. The RANK-RANKL-OPG System: A Multifaceted Regulator of Homeostasis, Immunity, and Cancer. Medicina (Kaunas). 2023;59(10):1752.
[21] WU LA, WANG F, DONLY KJ, et al. Establishment of Immortalized BMP2/4 Double Knock-Out Osteoblastic Cells Is Essential for Study of Osteoblast Growth, Differentiation, and Osteogenesis. J Cell Physiol, 2016;231(6):1189-1198.
[22] CHEN G, DENG C, LI YP. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci. 2012;8(2): 272-288.
[23] KARST M, GORNY G, GALVIN RJ, et al. Roles of stromal cell RANKL, OPG, and M-CSF expression in biphasic TGF-β regulation of osteoclast differentiation. J Cell Physiol. 2004;200(1):99-106.
[24] BENNETT CN, LONGO KA, WRIGHT WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sc U S A. 2005;102(9):3324-3329.
[25] FITZGERALD KA, KAGAN JC. Toll-like Receptors and the Control of Immunity. Cell. 2020;180(6):1044-1066.
[26] GRAVES D. Cytokines that promote periodontal tissue destruction. J Periodontol. 2008;79:1585-1591.
[27] CHI H, PEPPER M, THOMAS PG. Principles and therapeutic applications of adaptive immunity. Cell. 2024;187(9):2052-2078.
[28] KAWAI T, MATSUYAMA T, HOSOKAWA Y, et al. B and T lymphocytes are the primary sources of RANKL in the bone resorptive lesion of periodontal disease. Am J Pathol. 2006;169: 987-998.
[29] JELJELI MM, ADAMOPOULOS IE. Innate immune memory in inflammatory arthritis. Nat Rev Rheumatol. 2023;19(10): 627-639.
[30] PACIOS S, XIAO W, MATTOS M, et al. Osteoblast lineage cells play an essential role in periodontal bone loss through activation of nuclear factor-kappa B. Sci Rep. 2015;5:16694.
[31] GUO Q, JIN Y, CHEN X, et al. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduct Target Ther. 2024;9(1):53.
[32] CHANG J, WANG Z, TANG E, et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med. 2009;15:682-689.
[33] JIMI E, AOKI K, SAITO H, et al. Selective inhibition of NF-[kappa]B blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nat Med. 2004;10:617-624.
[34] REDLICH K, GÖRTZ B, HAYER S, et al. Repair of local bone erosions and reversal of systemic bone loss upon therapy with anti-tumor necrosis factor in combination with osteoprotegerin or parathyroid hormone in tumor necrosis factor-mediated arthritis. Am J Pathol. 2004;164:543-555.
[35] HAUGEBERG G, CONAGHAN PG, QUINN M, et al. Bone loss in patients with active early rheumatoid arthritis: infliximab and methotrexate compared with methotrexate treatment alone. Explorative analysis from a 12-month randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2009;68:1898-1901.
[36] FRANZOSO G, CARLSON L, XING L, et al. Requirement for NF-κB in osteoclast and B-cell development. Genes & Development. 1997;11(24):3482-3496.
[37] RUOCCO MG, MAEDA S, PARK JM, et al. IκB kinase (IKK)β, but not IKKα, is a critical mediator of osteoclast survival and is required for inflammation-induced bone loss. J Exp Med. 2005;201:1677-1687.
[38] TAGANOV KD, BOLDIN MP, CHANG KJ, et al. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006; 103(33):12481-12486.
[39] TSITSIOU E, LINDSAY MA. microRNAs and the immune response. Curr Opin Pharmacol. 2009;9(4):514-520.
[40] PERRY MM, MOSCHOS SA, WILLIAMS AE. et al. Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells. J Immunol. 2008;180(8):5689-5698.
[41] WILLIAMS AE, PERRY MM, MOSCHOS SA, et al. Role of miRNA-146a in the regulation of the innate immune response and cancer. Biochem Soc Trans. 2008;36(Pt 6):1211-1215.
[42] LUKIW WJ, ZHAO Y, CUI JG. An NF-kappaB-sensitive microRNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 2008;283(46):31315-31322.
[43] LEE RC, FEINBAUM RL, AMBROS V, et al. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75(5):843-854.
[44] MACFARLANE LA, MURPHY PR. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010;11(7):537-561.
[45] LIU H, YUE X, ZHANG G, et al. Downregulation of miR-146a inhibits osteoporosis in the jaws of ovariectomized rats by regulating the Wnt/β-catenin signaling pathway. Int J Mol Med. 2021; 47(3):6.
[46] SAFERDING V, HOFMANN M, BRUNNER JS, et al. microRNA‐146a controls age‐related bone loss. Aging Cell. 2020;19(11):e13244.
[47] NAKASA T, SHIBUYA H, NAGATA Y, et al. The inhibitory effect of microRNA-146a expression on bone destruction in collagen-induced arthritis. Arthritis Rheum. 2011;63(6):1582-1590.
[48] LIU S, YANG H, HU B, et al. Sirt1 regulates apoptosis and extracellular matrix degradation in resveratrol-treated osteoarthritis chondrocytes via the Wnt/β-catenin signaling pathways. Exp Ther Med. 2017;14(5):5057-5062.
[49] TSUKASAKI M. RANKL and osteoimmunology in periodontitis. J Bone Miner Metab. 2021; 39(1):82-90.
[50] GHOTLOO S, MOTEDAYYEN H, AMANI D, et al. Assessment of microRNA‐146a in generalized aggressive periodontitis and its association with disease severity. J Periodontal Res. 2019;54(1):27-32.
[51] 钟秋,陈艳莉,冷建琼,等.龈沟液中miR-146a、miR-21表达水平与种植体周围炎的相关性研究[J].中国现代医药杂志,2022,24(9):34-37.
[52] ZHAO J, HUANG M, ZHANG X, et al. MiR‐146a Deletion Protects From Bone Loss in OVX Mice by Suppressing RANKL/OPG and M‐CSF in Bone Microenvironment. J Bone Miner Res. 2019;34(11):2149-2161.
[53] LIU L, YU F, LI L, et al. Bone marrow stromal cells stimulated by strontium-substituted calcium silicate ceramics: release of exosomal miR-146a regulates osteogenesis and angiogenesis. Acta Biomater. 2021;119: 444-457.
[54] DU J, NIU X, WANG Y, et al. MiR-146a-5p suppresses activation and proliferation of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis through directly targeting Wnt1 and Wnt5a. Sci Rep. 2015; 5:16163.
[55] ZHUANG X, ZHANG H, LI X, et al. Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1. Nat Cell Biol. 2017;19(10):1274-1285.
[56] YANG X, JIANG T, WANG Y, et al. The Role and Mechanism of SIRT1 in Resveratrol-regulated Osteoblast Autophagy in Osteoporosis Rats. Sci Rep. 2019;9(1):18424.
[57] ZHENG M, TAN J, LIU X, et al. miR-146a-5p targets Sirt1 to regulate bone mass. Bone Rep. 2021;14:101013.
[58] DANKS L, KOMATSU N, GUERRINI MM, et al. RANKL expressed on synovial fibroblasts is primarily responsible for bone erosions during joint inflammation. Ann Rheum Dis. 2016;75(6):1187-1195.
[59] KAWAI T, MATSUYAMA T, HOSOKAWA Y, et al. B and T Lymphocytes Are the Primary Sources of RANKL in the Bone Resorptive Lesion of Periodontal Disease. Am J Pathol. 2006;169(3):987-998.
[60] SAFERDING V, PUCHNER A, GONCALVES-ALVES E, et al. MicroRNA-146a governs fibroblast activation and joint pathology in arthritis. J Autoimmun. 2017;82:74-84.
[61] LI S, YUE Y, XU W, et al. MicroRNA-146a Represses Mycobacteria-Induced Inflammatory Response and Facilitates Bacterial Replication via Targeting IRAK-1 and TRAF-6. Plos One. 2013;8(12):e81438.
[62] HA H, HAN D, CHIO Y. Traf-mediated TNFR-family signaling. Curr Protoc Immunol. 2009;Chapter 11:Unit11.9D.
[63] JIANG S, HU Y, DENG S, et al. miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6. Biochim Biophys Acta Mol Basis Dis. 2018;1864(3): 925-933.
[64] MARSELL R, EINHORN TA. The biology of fracture healing. Injury. 2011;42(6):551-555.
[65] BAHNEY CS, ZONDERVAN RL, ALLISON P, et al. Cellular biology of fracture healing. J Orthop Res. 2019;37(1):35-50.
[66] ZURA R, XIONG Z, EINHORN T, et al. Epidemiology of Fracture Nonunion in 18 Human Bones. JAMA Surg. 2016;151(11): e162775.
[67] XIE Q, WEI W, RUAN J, et al. Effects of miR-146a on the osteogenesis of adipose-derived mesenchymal stem cells and bone regeneration. Sci Rep. 2017;7:42840.
[68] HAO ZC, LU J, WANG SZ, et al. Stem cell-derived exosomes: A promising strategy for fracture healing. Cell Prolif. 2017;50(5): e12359.
[69] PHINNEY DG, PITTENGER MF. Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells. 2017;35(4):851-858.
[70] QI X, ZHANG J, YUAN H, et al. Exosomes Secreted by Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Repair Critical-Sized Bone Defects through Enhanced Angiogenesis and Osteogenesis in Osteoporotic Rats. Int J Biol Sci. 2016; 12(7):836-849.
[71] LIANG B, LIANG JM, DING JN, et al. Dimethyloxaloylglycine-stimulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/mTOR pathway. Stem Cell Res Ther. 2019;10(1):335.
[72] KOTNIK T, FREY W, SACK M, et al. Electroporation-based applications in biotechnology. Trends Biotechnol. 2015; 33(8):480-488.
[73] ZHOU X, YE C, JIANG L, et al. The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization. Mol Cell Endocrinol. 2024; 579:112089.
[74] ZHAI M, ZHU Y, YANG M, et al. Human Mesenchymal Stem Cell Derived Exosomes Enhance Cell-Free Bone Regeneration by Altering Their miRNAs Profiles. Adv Sci (Weinh). 2020;7(19):2001334.
[75] YANG J, SHUAI J, SIOW L, et al. MicroRNA-146a-loaded magnesium silicate nanospheres promote bone regeneration in an inflammatory microenvironment. Bone Res. 2024;12(1):2.
[76] WANG Y, WU J, FENG J, et al. From Bone Remodeling to Wound Healing: An miR-146a-5p-Loaded Nanocarrier Targets Endothelial Cells to Promote Angiogenesis. ACS Appl Mater Interfaces. 2024;16(26):32992-33004.
[77] HANKENSON KD, GAGNE K, SHAUGHNESSY M. Extracellular signaling molecules to promote fracture healing and bone regeneration. Adv Drug Deliv Rev. 2015; 94:3-12.
[78] RAMASAMY SK, KUSUMBE AP, ITKIN T, et al. Regulation of Hematopoiesis and Osteogenesis by Blood Vessel-Derived Signals. Annu Rev Cell Dev Biol. 2016;32: 649-675.
[79] NAN K, PEI JP, FAN LH, et al. Resveratrol prevents steroid‐induced osteonecrosis of the femoral head via miR‐146a modulation. Ann N Y Acad Sci. 2021;1503(1):23-37.
[80] BHATTARAI G, POUDEL SB, KOOK SH, et al. Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis. Acta Biomater. 2016;29:398-408.
[81] D’AUTRÉAUX B, TOLEDANO MB. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007;8(10):813-824.
[82] CALLAWAY DA, JIANG JX. Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. J Bone Miner Metab. 2015; 33(4):359-370.
[83] ZHANG J, WANG X, VIKASH V, et al. ROS and ROS-mediated cellular signaling. Oxid Med Cell Longev. 2016;2016:4350965.
[84] ALMEIDA M, HAN L, MARTIN-MILLAN M, et al. Oxidative Stress Antagonizes Wnt Signaling in Osteoblast Precursors by Diverting β-Catenin from T Cell Factor- to Forkhead Box O-mediated Transcription. J Biol Chem. 2007;282(37):27298-27305.
[85] 杨彬,程韶,杨顺,等.基于miR-146a-5p/Notch1信号通路探讨补肾壮筋汤对骨质疏松小鼠骨密度及成骨分化的影响[J].药物评价研究,2025,48(1):73-84.
[86] HE L, ZHOU Q, ZHANG H, et al. PF127 Hydrogel-Based Delivery of Exosomal CTNNB1 from Mesenchymal Stem Cells Induces Osteogenic Differentiation during the Repair of Alveolar Bone Defects. Nanomaterials (Basel). 2023;13(6):1083.
[87] ZHOU X, MOUSSA FM, MANKOCI S, et al. Orthosilicic acid, Si(OH)4, stimulates osteoblast differentiation in vitro by upregulating miR-146a to antagonize NF-κB activation. Acta Biomater. 2016;39:192-202.
[88] LIU L, YU F, LI L, et al. Bone marrow stromal cells stimulated by strontium-substituted calcium silicate ceramics: release of exosomal miR-146a regulates osteogenesis and angiogenesis. Acta Biomater. 2021;119: 444-457.
[89] CAO G, MENG X, HAN X, et al. Exosomes derived from circRNA Rtn4-modified BMSCs attenuate TNF-α-induced cytotoxicity and apoptosis in murine MC3T3-E1 cells by sponging miR-146a. Biosci Rep. 2020;40(5): BSR20193436.
[90] REN Y, WANG S, LI H, et al. Low-energy red light-emitting diode irradiation enhances osteogenic differentiation of periodontal ligament stem cells by regulating miR-146a-5p. J Periodontal Res. 2024;59(5):1031-1041.

引言

材料方法

1.1 研究设计见图1。
1.2 资料来源
1.2.1 检索人及检索时间作者于2025年4月进行检索。
1.2.2 检索文献时限 2000年1月至2025年4月。
1.2.3 检索数据库中国知网、PubMed和Web of Science数据库。
1.2.4 检索词中文检索词为“微小RNA-146a，骨，骨代谢，成骨细胞，破骨细胞，骨组织再生”。英文检索词为“microRNA-146a，Bone metabolism，Osteoblast，Osteoclast，Bone regeneration”。
1.2.5 检索文献类型类型不限。
1.2.6 检索策略 (包括中英文检索词、检索词的逻辑组配等)详见图2。
1.2.7 检索文献量共检索到文献
11 230篇，其中中国知网数据库检索到中文文献988篇，PubMed数据库检索到英文文献5 952篇，Web of Science数据库检索到英文文献4 290篇。
1.3 入组标准
1.3.1 纳入标准 ①对骨代谢过程及其影响因素进行研究的相关文献；②探讨参与骨代谢的关键细胞如何调控骨代谢的相关文献；③探究miR-146a如何调控骨代谢过程、骨代谢关键细胞生物学行为的相关文献；④miR-146a应用于维持骨稳态、促进骨组织修复再生的新研究进展、应用效果显著且关联度较高的相关文献。

1.3.2 排除标准 ①内容相关度低、重复性高、较陈旧的文献；②实验设计不严密，研究结果可信度较差、论

证不充分的文献；③实验样本量不足、缺少可重复性的文献。

1.4 文献质量评估与数据提取根据文献排除标准筛选出与该综述主题密切相关且研究新颖、数据真实可信、论证充分、具有临床应用价值的文献进行总结讨论，最终共纳入90篇符合标准的文献进行综述，其中中文文献2篇，英文文献88篇，检索流程详见图3。

讨论

miR-146a可在牙周炎、骨关节炎、骨质疏松等多种骨代谢相关疾病中异常表达。miR-146a作为一个多功能miRNA，可在不同细胞内发挥重要作用。miR-146a不仅能通过调节Wnt/β-catenin、骨形态发生蛋白/Smads信号通路抑制骨髓间充质干细胞分化为成骨细胞，还可通过调节核因子ΚB受体活化因子配体、核因子κB信号通路抑制髓系单核细胞分化成破骨细胞，也能直接作用于成骨细胞进而影响其细胞活性及其对破骨细胞的作用，或通过调节免疫反应间接影响成骨细胞和破骨细胞的活性。因而，miR-146a有望成为兼具诊断和治疗价值的靶点。
然而，miR-146a 在骨代谢调控中的复杂性引发了诸多需要深入探究的问题。不同骨代谢疾病患者体液中，miR-146a的表达水平呈现显著异质性。骨质疏松患者血清中miR-146a水平与骨质疏松的严重程度呈正相关，而牙周炎、骨关节炎患者的龈沟液、关节滑膜液中miR-146a水平与疾病的进展无明确的正/负相关，可受疾病炎症强度与细胞类型调控。这种差异可能源于不同组织微环境中免疫细胞/基质细胞对核因子κB通路的响应程度不同，或不同疾病阶段miR-146a活性不同，如急性炎症期可激活miR-146a的负反馈调节，进而抑制核因子κB通路传导，使miR-146a转录水平降低；而慢性期miR-146a的负反馈调节受限，miR-146a则持续高表达。由于miR-146a对成骨细胞、破骨细胞均具有调控作用，miR-146a 因而具备成骨调控双面性，这种双面性可能主要依赖于炎症微环境的强度。在生理状态或轻度炎症下，miR-146a 通过靶向Smad4、沉默信息调节因子2相关酶1等直接抑制成骨细胞形成及活性，表现为“成骨抑制性”；而在过度炎症(如脂多糖刺激)时，其通过抑制核因子κB通路减少促炎因子释放，解除炎症对骨髓间充质干细胞成骨分化的抑制，同时其通过抑制核因子κB减少破骨细胞形成，因而表现为“成骨促进性”。这种双面性的核心在于miR-146a可同时参与“细胞自主分化调控”和“炎症微环境调节”。此外，在口腔微生态中，miR-146也可能通过调控宿主免疫应答影响菌种互作。如牙龈卟啉单胞菌等牙周致病菌分泌的脂多糖可激活 Toll样受体4/核因子κB 通路，诱导免疫细胞高表达miR-146a，而miR-146a通过负反馈调节靶向白细胞介素1受体相关激酶1、肿瘤坏死因子受体相关因子6，抑制Toll样受体4/核因子κB通路传导，下调炎症因子肿瘤坏死因子α、白细胞介素1β、白细胞介素6，因而间接抑制致病菌过度增殖，维持菌群平衡，避免炎症性骨代谢疾病进展。
基于miR-146a调节骨代谢的突出作用，可通过递送miR-146a模拟物或拮抗剂直接改变相应细胞内的miR-146a水平，缓解骨代谢相关疾病进程，促进骨组织修复；也可利用某些新型药物或生物材料影响机体细胞表达miR-146a的能力，间接改变细胞内miR-146a水平，调控骨代谢。然而，miR-146a仍存在诸多临床转化难点。由于miR-146a模拟物及拮抗剂分子质量小、稳定性差、靶点众多等原因，其在递送过程中易降解、缺乏靶向性，因而直接使用miR-146a模拟物和/或拮抗物的治疗手段缺乏有效性及组织特异性，且其在体内应用的远期安全性仍需进一步探究。此外miR-146a剂量调控困难，miR-146a 表达过高可能过度抑制成骨，过低则无法有效控制炎症，需结合疾病分期动态调整剂量。因而，目前应继续开发更为安全、高效、靶向、智能响应型(如炎症因子敏感释放)的miR-146a模拟物/抑制剂递送体系，通过调控机体特定细胞内的miR-146a水平及其下游相关信号通路，从而实现原位骨组织再生。同时应不断完善miR-146a骨代谢调控网络，以促进miR-146a在骨代谢相关疾病和骨组织工程中的应用。
中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

文章快阅

延伸阅读

文章特点：该文章具有较强的系统性，通过检索中国知网、PubMed、Web of Science三大数据库2000-2025年的文献，经严格筛选纳入90篇核心文献，系统梳理了microRNA-146a (miR-146a)对骨代谢的调控机制和其在骨组织工程中的应用。且文章机制阐述全面，涵盖Wnt/β-catenin、骨形态发生蛋白/Smads、核因子κB等多条骨代谢关键信号通路，并解析miR-146a对这些信号通路的调控作用，揭示了其通过调节成骨-破骨细胞分化、相互作用和炎症微环境直接/间接调控骨代谢的重要作用。#br# 研究意义：该文章具有较强的理论价值，明确miR-146a在骨质疏松、骨关节炎、牙周炎等疾病中的异常表达机制，为理解骨代谢失衡的分子基础提供了新视角。且该文章具有一定的临床应用潜力，提出了miR-146a作为骨代谢疾病诊疗靶点的可能性，为开发靶向治疗策略(如模拟物/拮抗剂)和骨组织工程技术奠定了理论基础。#br# 文章创新点：文章首次系统整合miR-146a对成骨细胞与破骨细胞的双向调控网络，突出其“既抑制成骨又抑制破骨”的独特作用模式及与炎症微环境的交叉调控。该文章将miR-146a的免疫调节功能与骨代谢结合，揭示其在炎症性骨疾病中的“免疫-骨代谢”调控枢纽作用，拓展了骨免疫学研究视角，实现跨领域关联。且该文章聚焦外泌体、纳米载体、3D支架等新型递送系统在miR-146a靶向递送中的应用，同时提出小分子药物、中药等间接调控策略，具备充分的应用探索，为临床转化提供了多元思路。

微小RNA-146a调节骨代谢在骨组织工程中的应用

microRNA-146a regulates bone metabolism and its application in bone tissue engineering

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

引言

材料方法

讨论

文章快阅

延伸阅读

编辑推荐

Metrics

本文评价

[1]	陈豪杰, 王黛, 沈山. 种植体周围炎中的免疫炎症微环境机制[J]. 中国组织工程研究, 2026, 30(8): 2054-2062.
[2]	王峥, 程吉, 于金龙, 刘文红, 王召红, 周鲁星. 水凝胶材料在脑卒中治疗中的应用进展与未来展望[J]. 中国组织工程研究, 2026, 30(8): 2081-2090.
[3]	蔡子鸣, 于庆贺, 马鹏飞, 张鑫, 周龙千, 张崇阳, 林文平. 血红素氧合酶1减轻脂多糖诱导髓核间充质干细胞的炎症反应[J]. 中国组织工程研究, 2026, 30(7): 1624-1631.
[4]	何家乐, 黄茜, 董鸿斐, 陈朗, 钟方宇, 李先慧. 脱细胞真皮基质联合脂肪干细胞外泌体促进烧伤创面愈合[J]. 中国组织工程研究, 2026, 30(7): 1699-1710.
[5]	夏林枫, 王露, 龙乾发, 唐荣武, 罗浩东, 汤轶, 钟俊, 刘阳. 人脐带间充质干细胞来源外泌体减轻脓毒症脑病小鼠血脑屏障损伤[J]. 中国组织工程研究, 2026, 30(7): 1711-1719.
[6]	崔连旭, 李昊旻, 许峻荣, 谭宝东, 陆大鸿, 彭四维, 王进辉. 脐带间充质干细胞条件培养基对小型猪创伤性颅脑损伤组织修复的影响[J]. 中国组织工程研究, 2026, 30(7): 1730-1735.
[7]	陈钰璘, 何莹莹, 胡凯, 陈枝凡, 聂莎, 蒙衍慧, 李闰珍, 张小朵, 李宇稀, 唐耀平. 瓜蒌类外泌体囊泡防治动脉粥样硬化的作用及机制[J]. 中国组织工程研究, 2026, 30(7): 1768-1781.
[8]	曹涌, 滕虹良, 邰鹏飞, 李骏达, 朱腾旗, 李兆进. 细胞因子和卫星细胞在肌肉再生中的相互作用[J]. 中国组织工程研究, 2026, 30(7): 1808-1817.
[9]	潘鸿飞, 庄圳冰, 徐白云, 杨章阳, 林恺瑞, 詹冰晴, 蓝靖涵, 高恒, 张南波, 林家煜. 不同浓度金诺芬抑制M1型巨噬细胞功能及修复糖尿病小鼠伤口的价值[J]. 中国组织工程研究, 2026, 30(6): 1390-1397.
[10]	彭志伟, 陈雷, 佟磊. 木犀草素促进糖尿病小鼠创面愈合的作用与机制[J]. 中国组织工程研究, 2026, 30(6): 1398-1406.
[11]	侯超文, 李兆进, 孔健达, 张树立. 骨骼肌衰老主要生理变化及运动的多机制调控作用[J]. 中国组织工程研究, 2026, 30(6): 1464-1475.
[12]	孙尧天, 徐凯, 王沛云. 运动影响铁代谢对免疫性炎症疾病调控的潜在机制[J]. 中国组织工程研究, 2026, 30(6): 1486-1498.
[13]	油惠娟, 吴姝臻, 荣融, 陈立沅, 赵玉晴, 王清路, 欧小伟, 杨风英. 巨噬细胞自噬与肺部疾病：作用的两面性[J]. 中国组织工程研究, 2026, 30(6): 1516-1526.
[14]	温广伟, 甄颖豪, 郑泰铿, 周淑怡, 莫国业, 周腾鹏, 李海山, 赖以毅. 异银杏素对破骨细胞分化的影响和机制[J]. 中国组织工程研究, 2026, 30(6): 1348-1358.
[15]	张迪, 赵君, 马广悦, 孙晖, 蒋蓉. 基于高通量测序技术分析慢性社会挫败应激小鼠抑郁样行为的作用机制[J]. 中国组织工程研究, 2026, 30(5): 1139-1146.