MicroRNAs in Aseptic Loosening of Prosthesis: Pathophysiology and Potential Therapeutic Approaches

Document Type : SCOPING REVIEW

Authors

1 Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Department of Orthopedics, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Babol University of Medical Sciences, Babol, Iran

4 Anesthesiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Objectives: Aseptic loosening (AL) is one of the leading causes of total joint arthroplasty (TJA) revision. 
Discovering the roles of microRNAs (miRNA/miR) in ontogenesis and osteolysis has attracted more 
attention to diagnosing and treating bone disorders. This review aimed to summarize miRNA biogenesis 
and describe the involvement of miRNAs in AL of implants.
Methods: A detailed search was carried out on scientific search engines, including Google Scholar, Web of Science, 
and PubMed, to find appropriate papers related to subjects. The search process was performed using the following 
keywords: "Implant", "miRNAs", "Wear particles", "Osteoclasts", "Total joint replacement", and "Osteolytic diseases".
Results: miRNAs play an essential role in the regulation of gene expression. AL is associated with several 
pathologic properties, including wear particle-induced persistent inflammatory response, unbalanced 
osteoclastogenesis, abnormal osteoblast differentiation, and maturation. Recent researches have revealed that 
these pathological events are closely associated with miRNA deregulation, confirming the relationship between 
miRNA and AL of prostheses.
Conclusion: With the results of the new approaches to target miRNA, the essential role of miRNA is further defined. 
Understanding the mechanisms of miRNAs and related signaling pathways in the pathophysiology of AL will help 
scientists illuminate novel therapeutic strategies and specific targeted drugs.
 Level of evidence: V

Keywords

Main Subjects


1. Sayan A, Kopiec A, Shahi A, Chowdhry M, Bullock M, 
Oliashirazi A. The Expanding Role of Biomarkers in 
Diagnosing Infection in Total Joint Arthroplasty: A Review of 
Current Literature. Arch Bone Jt Surg. 2021; 9:33-43 doi: 
10.22038/abjs.2020.42989.2169.
2 Kaya C, Seyman CC,Kaya Y. Determination of the effect of 
preoperative knee joint function on postoperative quality of 
life in patients with total knee arthroplasty. J Orthop 
Res.2024. doi: 10.1002/jor.25876. 
3 Djahani O, Rainer S, Pietsch M,Hofmann S. Systematic analysis 
of painful total knee prosthesis, a diagnostic algorithm. Arch 
Bone Jt Surg. 2013; 1:48-52.
4 Abu-Amer Y, Darwech I,Clohisy JC. Aseptic loosening of total 
joint replacements: mechanisms underlying osteolysis and 
potential therapies. Arthritis Res Ther. 2007; 9 Suppl 1(Suppl 
1):S6. doi: 10.1186/ar2170.
5 Dyskova T, Kriegova E, Slobodova Z, et al. Inflammation timeaxis in aseptic loosening of total knee arthroplasty: A 
preliminary study. PLoS One. 2019; 14(8):e0221056. doi: 
10.1371/journal.pone.0221056.
6 Pakos EE, Paschos NK,Xenakis TA. Long Term Outcomes of 
Total Hip Arthroplasty in Young Patients under 30. Arch Bone 
Jt Surg. 2014; 2:157-162.
7 Hodges NA, Sussman EM,Stegemann JP. Aseptic and septic 
prosthetic joint loosening: Impact of biomaterial wear on 
immune cell function, inflammation, and infection. 
Biomaterials.2021:278:121127. doi: 
10.1016/j.biomaterials.2021.121127.
8 Purdue PE, Koulouvaris P, Nestor BJ,Sculco TP. The central 
role of wear debris in periprosthetic osteolysis. HSS J.2006; 
2(2):102-13. doi: 10.1007/s11420-006-9003-6.
9 Tahamtan A, Teymoori-Rad M, Nakstad B,Salimi V. Antiinflammatory microRNAs and their potential for 
inflammatory diseases treatment. Front 
Immunol.2018:9:1377. doi: 10.3389/fimmu.2018.01377.
10 Felekkis K, Touvana E, Stefanou C,Deltas C. microRNAs: a 
newly described class of encoded molecules that play a role in 
health and disease. Hippokratia .2010; 14:236-240.
11 Gámez B, Rodriguez-Carballo E,Ventura FJJome. MicroRNAs 
and post-transcriptional regulation of skeletal development. J 
Mol Endocrinol.2014; 52(3):R179-97. doi: 10.1530/JME-13-
0294.
12 Shin VY,Chu K-M. MiRNA as potential biomarkers and 
therapeutic targets for gastric cancer. World J 
Gastroenterol.2014; 20(30):10432-9. doi: 
10.3748/wjg.v20.i30.10432.
13 Ying SY, Chang DC,Lin SL. The microRNA (miRNA): overview 
of the RNA genes that modulate gene function. Mol 
Biotechnol.2008; 38(3):257-68. doi: 10.1007/s12033-007-
9013-8.
14 Ramalingam P, Palanichamy JK, Singh A, et al. Biogenesis of 
intronic miRNAs located in clusters by independent 
transcription and alternative splicing. RNA.2014; 20(1):76-
87. doi: 10.1261/rna.041814.113.
15 Tanzer A,Stadler PF. Molecular evolution of a microRNA 
cluster. J Mol Biol. 2004; 339(2):327-35. doi: 
10.1016/j.jmb.2004.03.065.
16 Lee Y, Kim M, Han J, et al. MicroRNA genes are transcribed by 
RNA polymerase II. EMBO J.2004; 23(20):4051-60. doi: 
10.1038/sj.emboj.7600385.
17 Medley JC, Panzade G,Zinovyeva AY. microRNA strand 
selection: Unwinding the rules. Wiley Interdiscip Rev 
RNA.2021; 12(3):e1627. doi: 10.1002/wrna.1627.
18 Zeng L, Jiang H-L, Ashraf GM, Li Z-R,Liu RJNRR. MicroRNA and 
mRNA profiling of cerebral cortex in a transgenic mouse 
model of Alzheimer's disease by RNA sequencing. Neural 
Regen Res.2021; 16(10):2099-2108. doi: 10.4103/1673-
5374.308104.
19 von Knoch M, Wedemeyer C, Pingsmann A, et al. The decrease 
of particle-induced osteolysis after a single dose of 
bisphosphonate. Biomaterials 2005; 26:1803-1808. doi: 
10.1016/j.biomaterials.2004.06.010.
20 Kandahari AM, Yang X, Laroche KA, Dighe AS, Pan D, Cui Q. A 
review of UHMWPE wear-induced osteolysis: the role for 
early detection of the immune response. Bone 
Res.2016:4:16014. doi: 10.1038/boneres.2016.14.
21 Fokter S, eds. Recent advances in arthroplasty. 1st ed. 
IntechOpen; 2012.
22 Wang S, Deng Z, Ma Y, et al. The Role of Autophagy and 
Mitophagy in Bone Metabolic Disorders. Int J Biol Sci .2020; 
16:2675-2691. doi: 10.7150/ijbs.46627.
23 Qiu J, Peng P, Xin M, et al. ZBTB20-mediated titanium particleinduced peri-implant osteolysis by promoting macrophage 
inflammatory responses. Biomater Sci.2020; 8(11):3147-
3163. doi: 10.1039/d0bm00147c.
24 Vijay K. Toll-like receptors in immunity and inflammatory 
diseases: Past, present, and future. Int Immunopharmacol. 
2018; 59:391-412. doi: 10.1016/j.intimp.2018.03.002.
25 Maitra R, Clement CC, Crisi GM, Cobelli N,Santambrogio L. 
Immunogenecity of modified alkane polymers is mediated 
through TLR1/2 activation. PLoS One. 2008; 3:e2438. doi: 
10.1371/journal.pone.0002438.
26 Ingham E,Fisher J. The role of macrophages in osteolysis of 
total joint replacement. Biomaterials. 2005; 26(11):1271-86. 
doi: 10.1016/j.biomaterials.2004.04.035.
27 Hameister R, Lohmann CH, Dheen ST, Singh G,Kaur C. The 
effect of TNF-α on osteoblasts in metal wear-induced 
periprosthetic bone loss. Bone Joint Res. 2020; 9:827-839. 
doi: 10.1302/2046-3758.911.bjr-2020-0001.r2.
28 Swanson KV, Deng M,Ting JPY. The NLRP3 inflammasome: 
molecular activation and regulation to therapeutics. Nat Rev 
Immunol.2019; 19(8):477-489. doi: 10.1038/s41577-019-
0165-0.
29 Meng J, Zhou C, Hu B, et al. Stevioside prevents wear particleinduced osteolysis by inhibiting osteoclastogenesis and 
inflammatory response via the suppression of TAK1 
activation. Front Pharmacol.2018:9:1053. doi: 
10.3389/fphar.2018.01053.
30 Terkawi MA, Kadoya K, Takahashi D, et al. Identification of IL27 as potent regulator of inflammatory osteolysis associated 
with vitamin E-blended ultra-high molecular weight 
polyethylene debris of orthopedic implants. Acta 
Biomater.2019:89:242-251. doi: 
10.1016/j.actbio.2019.03.028. 31 Hensley AP,McAlinden A. The role of microRNAs in bone 
development. Bone. 2021; 143:115760. doi: 
10.1016/j.bone.2020.115760.
32 Chen J, Qiu M, Dou C, Cao Z,Dong SJDDR. MicroRNAs in bone 
balance and osteoporosis. Drug Dev Res.2015; 76(5):235-45. 
doi: 10.1002/ddr.21260.
33 Hosseinpour S, He Y, Nanda A,Ye Q. MicroRNAs Involved in 
the Regulation of Angiogenesis in Bone Regeneration. Calcif 
Tissue Int.2019; 105(3):223-238. doi: 10.1007/s00223-019-
00571-8.
34 Lam J, Takeshita S, Barker JE, et al. TNF-α induces 
osteoclastogenesis by direct stimulation of macrophages 
exposed to permissive levels of RANK ligand. J Clin 
Invest.2000; 106(12):1481-8. doi: 10.1172/JCI11176.
35 van Wijnen AJ, van de Peppel J, van Leeuwen JP, et al. 
MicroRNA functions in osteogenesis and dysfunctions in 
osteoporosis. Curr Osteoporos Rep. 2013; 11(2):72-82. doi: 
10.1007/s11914-013-0143-6.
36 Kagiya T,Nakamura S. Expression profiling of microRNAs in 
RAW264.7 cells treated with a combination of tumor necrosis 
factor alpha and RANKL during osteoclast differentiation. J 
Periodontal Res. 2013; 48:373-385 doi: 10.1111/jre.12017.
37 Mizoguchi F, Izu Y, Hayata T, et al. Osteoclast-specific Dicer 
gene deficiency suppresses osteoclastic bone resorption. J 
Cell Biochem. 2010; 109:866-875. doi: 10.1002/jcb.22228.
38 Inoue K, Ng C, Xia Y,Zhao B. Regulation of Osteoclastogenesis 
and Bone Resorption by miRNAs. Front Cell Dev Biol. 2021; 
9:651161. doi: 10.3389/fcell.2021.651161.
39 Groven RVM, van Koll J, Poeze M, Blokhuis TJ,van Griensven 
M. miRNAs Related to Different Processes of Fracture 
Healing: An Integrative Overview. Front Surg. 2021; 
8:786564. doi: 10.3389/fsurg.2021.786564.
40 Gao H,Wang X. Serum miRNA‐142 and BMP‐2 are markers of 
recovery following hip replacement surgery for femoral neck 
fracture. Exp Ther Med.2020; 20(5):105. doi: 
10.3892/etm.2020.9235.
41 Li RW, Patel HR, Perriman D, Wang J, Smith PN. MicroRNA 
Profiling in Wear Particle Associated Osteolysis In 
Orthopaedic Proceedings. Bone & Joint. 2014; 
96(SUPP11):43-43.
42 Jiang Y, Ma H, Zhang Q, et al. Integrative analyses reveal RNA 
regulatory network in Ti particles induced inflammation. 
European Journal of Inflammation. 2021; 
19:20587392211044863.
43 Zheng DZ, Bu YM, Wang L,Liu J. MicroRNA-130b Promotes 
Wear Particle-Induced Osteolysis via Downregulating 
Frizzled-Related Protein (FRZB). Curr Neurovasc Res. 2017; 
14:32-38 .doi: 10.2174/1567202614666161123112409.
44 Zheng D-Z, Bu Y-M,Wang L. miR-130b participates in wear 
particle-induced inflammation and osteolysis via FOXF2/NFκB pathway. Immunopharmacol Immunotoxicol.2018; 
40(5):408-414. doi: 10.1080/08923973.2018.1514626.
45 Zhou Y, Liu Y,Cheng L. miR‐21 expression is related to 
particle‐induced osteolysis pathogenesis. J Orthop Res.2012; 
30(11):1837-42. doi: 10.1002/jor.22128.
46 Zhang L, Zhao W, Bao D, et al. miR-9-5p promotes wearparticle-induced osteoclastogenesis through activation of the 
SIRT1/NF-κB pathway. 3 Biotech. 2021; 11:258. doi: 
10.1007/s13205-021-02814-8.
47 Lagos-Quintana M, Rauhut R, Lendeckel W,Tuschl T. 
Identification of novel genes coding for small expressed 
RNAs. Science. 2001; 294:853-858. doi: 
10.1126/science.1064921.
48 da Costa Martins PA,De Windt LJ. miR-21: a miRaculous 
Socratic paradox. Cardiovasc Res.2010; 87(3):397-400. doi: 
10.1093/cvr/cvq196.
49 Li X, Guo L, Liu Y, et al. MicroRNA-21 promotes osteogenesis 
of bone marrow mesenchymal stem cells via the Smad7-
Smad1/5/8-Runx2 pathway. Biochem Biophys Res Commun. 
2017; 493:928-933 doi: 10.1016/j.bbrc.2017.09.119.
50 Oka S, Li X, Zhang F, et al. MicroRNA-21 facilitates osteoblast 
activity. Biochem Biophys Rep. 2021; 25:100894 doi: 
10.1016/j.bbrep.2020.100894.
51 Li H, Yang F, Wang Z, Fu Q,Liang A. MicroRNA-21 promotes 
osteogenic differentiation by targeting small mothers against 
decapentaplegic 7. Mol Med Rep.2015; 12(1):1561-7. doi: 
10.3892/mmr.2015.3497.
52 Lian F, Zhao C, Qu J, et al. Icariin attenuates titanium particleinduced inhibition of osteogenic differentiation and matrix 
mineralization via miR-21-5p. Cell Biol Int. 2018; 42:931-939. 
doi: 10.1002/cbin.10957.
53 Wang S, Liu Z, Wang J, et al. miR‐21 promotes 
osteoclastogenesis through activation of PI3K/Akt signaling 
by targeting Pten in RAW264.7 cells. Mol Med Rep. 2020; 
21:1125-1132. doi: 10.3892/mmr.2020.10938.
54 Kriegel AJ, Liu Y, Fang Y, Ding X,Liang M. The miR-29 family: 
genomics, cell biology, and relevance to renal and 
cardiovascular injury. Physiol Genomics. 2012; 44:237-244. 
doi: 10.1152/physiolgenomics.00141.2011.
55 Wang FS, Chuang PC, Lin CL, et al. MicroRNA-29a protects 
against glucocorticoid-induced bone loss and fragility in rats 
by orchestrating bone acquisition and resorption. Arthritis 
Rheum. 2013; 65:1530-1540. doi: 10.1002/art.37948.
56 Rossi M, Pitari MR, Amodio N, et al. miR-29b negatively 
regulates human osteoclastic cell differentiation and function: 
implications for the treatment of multiple myeloma-related 
bone disease. J Cell Physiol. 2013; 228:1506-1515. doi: 
10.1002/jcp.24306.
57 Franceschetti T, Kessler CB, Lee SK,Delany AM. miR-29 
promotes murine osteoclastogenesis by regulating osteoclast 
commitment and migration. J Biol Chem. 2013; 288:33347-
33360. doi: 10.1074/jbc.M113.484568.
58 Bu Y-m, Zheng D-z, Wang L,Liu J. Abrasive endoprosthetic 
wear particles inhibit IFN-γ secretion in human monocytes 
via upregulating TNF-α-induced miR-29b. 
Inflammation.2017; 40(1):166-173. doi: 10.1007/s10753-
016-0465-5.
59 Concepcion CP, Bonetti C,Ventura A. The microRNA-17-92 
family of microRNA clusters in development and disease. 
Cancer J. 2012; 18:262-267. doi: 
10.1097/PPO.0b013e318258b60a.
60 Murata K, Ito H, Yoshitomi H, et al. Inhibition of miR‐92a 
enhances fracture healing via promoting angiogenesis in a 
model of stabilized fracture in young mice. J Bone Miner 
Res.2014; 29(2):316-26. doi: 10.1002/jbmr.2040.
61 Hu L, Liu J, Xue H, et al. miRNA-92a-3p regulates osteoblast 
differentiation in patients with concomitant limb fractures 
and TBI via IBSP/PI3K-AKT inhibition. Mol Ther Nucleic Acids.2021:23:1345-1359. doi: 10.1016/j.omtn.2021.02.008.
62 Yan X, Wang H, Li Y, et al. MicroRNA‐92a overexpression 
promotes the osteogenic differentiation of bone 
mesenchymal stem cells by impeding Smad6‐mediated 
runt‐related transcription factor 2 degradation. Mol Med 
Rep.2018; 17(6):7821-7826. doi: 10.3892/mmr.2018.8829..
63 Wen Z, Lin S, Li C, et al. MiR-92a/KLF4/p110δ regulates 
titanium particles-induced macrophages inflammation and 
osteolysis. Cell Death Discov.2022; 8(1):197. doi: 
10.1038/s41420-022-00999-2.
64 Fang T, Wu Q, Zhou L, Mu S, Fu QJEcr. miR-106b-5p and miR17-5p suppress osteogenic differentiation by targeting Smad5 
and inhibit bone formation. Exp Cell Res.2016; 347(1):74-82. 
doi: 10.1016/j.yexcr.2016.07.010.
65 Liu K, Jing Y, Zhang W, et al. silencing miR-106b accelerates 
osteogenesis of mesenchymal stem cells and rescues against 
glucocorticoid-induced osteoporosis by targeting BMP2. 
Bone. 2017; 97:130-138. doi: 10.1016/j.bone.2017.01.014.
66 Tao Y, Wang Z, Wang L, et al. Downregulation of miR-106b 
attenuates inflammatory responses and joint damage in 
collagen-induced arthritis. Rheumatology (Oxford). 2017; 
56:1804-1813. doi: 10.1093/rheumatology/kex233.
67 Tao Y, Wang Z, Wang L, et al. Downregulation of miR-106b 
attenuates inflammatory responses and joint damage in 
collagen-induced arthritis. Rheumatology (Oxford).2017; 
56(10):1804-1813. doi: 10.1093/rheumatology/kex233.
68 Yu B, Bai J, Shi J, et al. MiR-106b inhibition suppresses 
inflammatory bone destruction of wear debris-induced 
periprosthetic osteolysis in rats. J Cell Mol Med. 2020; 
24:7490-7503. doi: 10.1111/jcmm.15376.
69 Chen B, Yang W, Zhao H, et al. Abnormal expression of miR135b-5p in bone tissue of patients with osteoporosis and its 
role and mechanism in osteoporosis progression. Exp Ther 
Med. 2020; 19:1042-1050. doi: 10.3892/etm.2019.8278.
70 Schaap-Oziemlak AM, Raymakers RA, Bergevoet SM, et al. 
MicroRNA hsa-miR-135b regulates mineralization in 
osteogenic differentiation of human unrestricted somatic 
stem cells. Stem Cells Dev. 2010; 19:877-885 doi: 
10.1089/scd.2009.0112.
71 Li Z, Hassan MQ, Volinia S, et al. A microRNA signature for a 
BMP2-induced osteoblast lineage commitment program. Proc 
Natl Acad Sci U S A. 2008; 105:13906-13911. doi:
10.1073/pnas.0804438105.
72 Xu S, Cecilia Santini G, De Veirman K, et al. Upregulation of 
miR-135b is involved in the impaired osteogenic 
differentiation of mesenchymal stem cells derived from 
multiple myeloma patients. PLoS One.2013; 8(11):e79752. 
doi: 10.1371/journal.pone.0079752.
73 Zhang Y, Zhu Q, Fang Q, et al. LINC01534/miR-135b5p/PTPRT axis regulates inflammatory response in loosening 
total hip replacement via modulating NF-κB signaling 
pathway. Injury.2022; 53(6):1829-1836. doi: 
10.1016/j.injury.2022.03.022.
74 Pauley KM, Satoh M, Chan AL, et al. Upregulated miR-146a 
expression in peripheral blood mononuclear cells from 
rheumatoid arthritis patients. Arthritis Res Ther. 2008; 
10:R101. doi: 10.1186/ar2493.
75 Blüml S, Bonelli M, Niederreiter B, et al. Essential role of 
microRNA‐155 in the pathogenesis of autoimmune arthritis 
in mice. Arthritis Rheum.2011; 63(5):1281-8. doi: 
10.1002/art.30281.
76 Mizoguchi F, Izu Y, Hayata T, et al. Osteoclast‐specific Dicer 
gene deficiency suppresses osteoclastic bone resorption. J 
Cell Biochem.2010; 109(5):866-75. doi: 10.1002/jcb.22228.
77 Mann M, Barad O, Agami R, Geiger B,Hornstein E. miRNAbased mechanism for the commitment of multipotent 
progenitors to a single cellular fate. Proc Natl Acad Sci U S 
A.2010; 107(36):15804-9. doi: 10.1073/pnas.0915022107.
78 Zhang J, Zhao H, Chen J, et al. Interferon-β-induced miR-155 
inhibits osteoclast differentiation by targeting SOCS1 and 
MITF. FEBS Lett.2012; 586(19):3255-62. doi: 
10.1016/j.febslet.2012.06.047.
79 Li Y, Zhang L, Wang J, Zheng Y, Cui J, Yuan G. Tanshinone IIA 
attenuates polyethylene-induced osteolysis in a mouse 
model: The key role of miR-155-5p/FOXO3 axis. Journal of 
Functional Foods. 2021; 87:104784. doi: 
10.1016/j.jff.2021.104784.