Chinese Journal of Tissue Engineering Research ›› 2026, Vol. 30 ›› Issue (18): 4702-4712.doi: 10.12307/2026.752
Li Jiayin, Sui Lei, Li Yanjing
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:CLC Number:
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.
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| [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. |
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