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Extracellular vesicles as novel approaches for the treatment of osteoarthritis: a narrative review on potential mechanisms

Abstract

Osteoarthritis (OA) is a progressive degeneration of articular cartilage with involvement of synovial membrane, and subchondral bone. Current treatment approaches have focused on controlling the OA symptoms, pain, and inflammation. Recently, cell-based therapies, including the application of stem cells such as mesenchymal stem cells (MSCs), have been introduced for restoration of the articular cartilage. Despite promising outcomes, there are some limitations in the application of MSCs for OA treatment. It has been demonstrated that the regenerative potential of stem cells is related to the production of paracrine factors. Extracellular vehicles (EVs), the main component of cell secretome, are membrane-bounded structures that deliver biologically active agents. The delivery of molecules (e.g., nucleic acids, proteins, and lipids) leads to cell-to-cell communication and the alteration of cell functions. In this review, general characteristics of EVs, as well as their potential mechanisms in the prevention and treatment of OA were considered. Based on in vitro and in vivo studies, EVs have shown to contribute to cartilage regeneration via suppression of degenerative factors and regulation of chondrocyte function in the synthesis of extracellular matrix components. Also, they inhibit the progression of OA or protect the cartilage from degradation via their impact on inflammatory cytokines. The different signaling pathways of EVs against the pathologic features of OA were summarized in this review. According to the results obtained from several investigations, more investigations should be design to prove the safety and effectiveness of EVs in the treatment and prevention of OA progression.

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References

  1. Abramson SB, Attur M, Amin AR, Clancy R (2001) Nitric oxide and inflammatory mediators in the perpetuation of osteoarthritis. Curr Rheumatol Rep 3:535–541

    CAS  PubMed  Article  Google Scholar 

  2. Alizamir T, Akbari M, Mokhtari T, Hassanzadeh G (2017) Associated functional motor recovery induced by Intracerebroventricular (ICV) microinjection of Wharton’s jelly mesenchymal stem cells following brain ischemia/reperfusion injury in rat: decreased dark neurons and Bax gene expression in the cerebral corte. J Contemp Med Sci 3:12

    Google Scholar 

  3. Anderson HC, Mulhall D, Garimella R (2010) Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis. Lab Invest 90:1549–1557. https://doi.org/10.1038/labinvest.2010.152

    CAS  Article  PubMed  Google Scholar 

  4. Ansari MY, Ahmad N, Haqqi TM (2020) Oxidative stress and inflammation in osteoarthritis pathogenesis: Role of polyphenols. Biomed Pharmacother 129:110452. https://doi.org/10.1016/j.biopha.2020.110452

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Arab L et al (2020) Human embryonic derived neural progenitor cells improves neurological scores following brain ischemia/reperfusion: modulation of blood and brain tissue microRNA-210. J Contemp Med Sci 1594:93

    Google Scholar 

  6. Arslan E, Guler MO, Tekinay AB (2016) Glycosaminoglycan-mimetic signals direct the osteo/chondrogenic differentiation of mesenchymal stem cells in a three-dimensional peptide nanofiber extracellular. Matrix Mimetic Environ Biomacromol 17:1280–1291. https://doi.org/10.1021/acs.biomac.5b01637

    CAS  Article  Google Scholar 

  7. Bagherifard A et al (2015) Platelet-rich plasma injection for symptomatic knee osteoarthritis. J Res Orthop Sci 2:0–0

    Google Scholar 

  8. Bannuru RR, Vaysbrot EE, Sullivan MC, McAlindon TE (2014) Relative efficacy of hyaluronic acid in comparison with NSAIDs for knee osteoarthritis: a systematic review and meta-analysis. In: Seminars in arthritis and rheumatism, vol 5. Elsevier, pp 593–599

  9. Ben-David U, Mayshar Y, Benvenisty N (2011) Large-scale analysis reveals acquisition of lineage-specific chromosomal aberrations in human adult stem cells. Cell Stem Cell 9:97–102. https://doi.org/10.1016/j.stem.2011.06.013

    CAS  Article  PubMed  Google Scholar 

  10. Blagojevic M, Jinks C, Jeffery A, Jordan KP (2010) Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthr Cartil 18:24–33. https://doi.org/10.1016/j.joca.2009.08.010

    CAS  Article  Google Scholar 

  11. Börger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, Giebel B (2017) Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci 18:1450

    PubMed Central  Article  CAS  Google Scholar 

  12. Casado-Díaz A, Quesada-Gómez JM, Dorado G (2020) Extracellular vesicles derived from mesenchymal stem cells (MSC) in regenerative medicine: applications in skin wound healing. Front Bioeng Biotechnol 8:146

    PubMed  PubMed Central  Article  Google Scholar 

  13. Chahal J et al (2019) Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl Med 8:746–757

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen T-M, Chen Y-H, Sun HS, Tsai S-J (2019) Fibroblast growth factors: Potential novel targets for regenerative therapy of osteoarthritis . Chin J Physiol 62:2

    CAS  PubMed  Article  Google Scholar 

  15. Coggon D, Reading I, Croft P, McLaren M, Barrett D, Cooper C (2001) Knee osteoarthritis and obesity. Int J Obes 25:622–627

    CAS  Article  Google Scholar 

  16. Colombo M, Raposo G, Théry C (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30:255–289. https://doi.org/10.1146/annurev-cellbio-101512-122326

    CAS  Article  PubMed  Google Scholar 

  17. Cooper C et al (2019) Safety of oral non-selective non-steroidal anti-inflammatory drugs in osteoarthritis: what does the literature say? Drugs Aging 36:15–24

    PubMed  PubMed Central  Article  Google Scholar 

  18. Cosenza S, Ruiz M, Toupet K, Jorgensen C, Noël D (2017) Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep 7:16214. https://doi.org/10.1038/s41598-017-15376-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Courties A, Gualillo O, Berenbaum F, Sellam J (2015) Metabolic stress-induced joint inflammation and osteoarthritis. Osteoarthr Cartil 23:1955–1965

    CAS  Article  Google Scholar 

  20. Doyle LM, Wang MZ (2019) Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome. Isol Analy Cells 8:727. https://doi.org/10.3390/cells8070727

    CAS  Article  Google Scholar 

  21. Fafián-Labora J et al (2017) Effect of age on pro-inflammatory miRNAs contained in mesenchymal stem cell-derived extracellular vesicles. Sci Rep 7:43923. https://doi.org/10.1038/srep43923

    Article  PubMed  PubMed Central  Google Scholar 

  22. Felson DT (2013) Osteoarthritis as a disease of mechanics. Osteoarthr Cartil 21:10–15

    CAS  Article  Google Scholar 

  23. Fu Y, Karbaat L, Wu L, Leijten J, Both SK, Karperien M (2017) Trophic effects of mesenchymal stem cells in tissue regeneration . Tissue Eng Part B Rev 23:515–528. https://doi.org/10.1089/ten.TEB.2016.0365

    CAS  Article  PubMed  Google Scholar 

  24. Furuta T et al (2016) Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model stem. Cells Transl Med 5:1620–1630. https://doi.org/10.5966/sctm.2015-0285

    CAS  Article  Google Scholar 

  25. García-Romero N et al (2017) DNA sequences within glioma-derived extracellular vesicles can cross the intact blood–brain barrier and be detected in peripheral blood. of patients Oncotarget 8:1416–1428. https://doi.org/10.18632/oncotarget.13635

    Article  PubMed  Google Scholar 

  26. Gholamrezanezhad A et al (2011) In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol 38:961–967. https://doi.org/10.1016/j.nucmedbio.2011.03.008

    CAS  Article  PubMed  Google Scholar 

  27. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O (2009) Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA. activity Nature cell biology 11:1143–1149

    CAS  PubMed  Article  Google Scholar 

  28. Goldring MB (1999) The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res 40:1–11. https://doi.org/10.3109/03008209909005273

    CAS  Article  PubMed  Google Scholar 

  29. Goldring MB, Berenbaum F (2015) Emerging targets in osteoarthritis therapy. Curr Opin Pharmacol 22:51–63. https://doi.org/10.1016/j.coph.2015.03.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Goldring MB et al (2011) Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. Eur Cell Mater 21:202–220. https://doi.org/10.22203/ecm.v021a16

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Gowen A, Shahjin F, Chand S, Odegaard KE, Yelamanchili SV (2020) Mesenchymal stem cell-derived extracellular vesicles: challenges in clinical applications. Front Cell Dev Biol 8:149. https://doi.org/10.3389/fcell.2020.00149

    Article  PubMed  PubMed Central  Google Scholar 

  32. Harirforoosh S, Asghar W, Jamali F (2013) Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci 16:821–847

    PubMed  Article  Google Scholar 

  33. Heinegård D, Saxne T (2011) The role of the cartilage matrix in osteoarthritis. Nat Rev Rheumatol 7:50–56. https://doi.org/10.1038/nrrheum.2010.198

    CAS  Article  PubMed  Google Scholar 

  34. Henrotin Y, Kurz B, Aigner T (2005) Oxygen and reactive oxygen species in cartilage degradation: friends or foes? Osteoarthr Cartil 13:643–654. https://doi.org/10.1016/j.joca.2005.04.002

    CAS  Article  Google Scholar 

  35. Herberts CA, Kwa MS, Hermsen HP (2011) Risk factors in the development of stem cell therapy. J Transl Med 9:1–14

    Article  Google Scholar 

  36. Holm MM, Kaiser J, Schwab ME (2018) Extracellular vesicles: multimodal envoys in neural maintenance and repair. Trends Neurosci 41:360–372

    CAS  PubMed  Article  Google Scholar 

  37. Huang J, Zhao L, Chen D (2018) Growth factor signalling in osteoarthritis. Growth Factors 36:187–195. https://doi.org/10.1080/08977194.2018.1548444

    CAS  Article  PubMed  Google Scholar 

  38. Ijaz S, Mohammed I, Gholaminejhad M, Mokhtari T, Akbari M, Hassanzadeh G (2020) Modulating pro-inflammatory cytokines, tissue damage magnitude, and motor deficit in spinal cord injury with subventricular zone-derived extracellular vesicles. J Mol Neurosci 70:458–466

    CAS  PubMed  Article  Google Scholar 

  39. Im HJ et al (2010) Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model. Arthritis Rheum 62:2995–3005. https://doi.org/10.1002/art.27608

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Inoue H et al (2008) High levels of serum IL-18 promote cartilage loss through suppression of aggrecan synthesis. Bone 42:1102–1110. https://doi.org/10.1016/j.bone.2008.01.031

    CAS  Article  PubMed  Google Scholar 

  41. Jafari D, Malih S, Eslami SS, Jafari R, Darzi L, Tarighi P, Samadikuchaksaraei A (2019) The relationship between molecular content of mesenchymal stem cells derived exosomes and their potentials: opening the way for exosomes based therapeutics. Biochimie 165:76–89

    CAS  PubMed  Article  Google Scholar 

  42. Jiang YZ, Zhang SF, Qi YY, Wang LL, Ouyang HW (2011) Cell transplantation for articular cartilage defects: principles of past, present, and future practice. Cell Transpl 20:593–607

    Article  Google Scholar 

  43. Kazemi SM, Besheli LD, Eajazi A, Sajadi MRM, Okhovatpoor MA, Zanganeh RF, Minaei R (2011) Pseudo-patella baja after total knee arthroplasty. Med Sci Monitor 17:CR292

    Article  Google Scholar 

  44. Kern S, Eichler H, Stoeve J, Klüter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood or adipose tissue. Stem Cells 24:1294–1301

    CAS  PubMed  Article  Google Scholar 

  45. Keshtkar S, Azarpira N, Ghahremani MH (2018) Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine. Stem Cell Res Ther 9:63

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Khatab S et al (2018) Mesenchymal stem cell secretome reduces pain and prevents cartilage damage in a murine osteoarthritis model. Eur Cells Mater 36:218–230

    CAS  Article  Google Scholar 

  47. Kim J, Xu M, Xo R, Mates A, Wilson GL, Pearsall AW, Grishko V (2010) Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthr Cartil 18:424–432. https://doi.org/10.1016/j.joca.2009.09.008

    CAS  Article  Google Scholar 

  48. Kolhe R et al (2017) Gender-specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis. Sci Rep 7:2029. https://doi.org/10.1038/s41598-017-01905-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Kolhe R et al (2020) Sex-specific differences in extracellular vesicle protein cargo in synovial fluid of patients with osteoarthritis. Life 10:337

    PubMed Central  Article  CAS  Google Scholar 

  50. Lai RC et al (2010a) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222. https://doi.org/10.1016/j.scr.2009.12.003

    CAS  Article  PubMed  Google Scholar 

  51. Lai RC et al (2010b) Derivation and characterization of human fetal MSCs: an alternative cell source for large-scale production of cardioprotective microparticles. J Mol Cell Cardiol 48:1215–1224. https://doi.org/10.1016/j.yjmcc.2009.12.021

    CAS  Article  PubMed  Google Scholar 

  52. Lener T et al (2015) Applying extracellular vesicles based therapeutics in clinical trials: an ISEV position paper. J Extracell Vesicles 4:30087

    PubMed  Article  CAS  Google Scholar 

  53. Lepetsos P, Papavassiliou AG (2016) ROS/oxidative stress signaling in osteoarthritis. Biochim Biophys Acta 1862:576–591. https://doi.org/10.1016/j.bbadis.2016.01.003

    CAS  Article  PubMed  Google Scholar 

  54. Li J, Dong S (2016) The signaling pathways involved in chondrocyte differentiation and hypertrophic differentiation. Stem Cells Int 2016:2470351–2470351. https://doi.org/10.1155/2016/2470351

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Lister BJ, Poland M, DeLapp RE (1993) Efficacy of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 95:S2–S9

    Article  Google Scholar 

  56. Liu Y, Zou R, Wang Z, Wen C, Zhang F, Lin F (2018) Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochem J 475:3629–3638

    CAS  PubMed  Article  Google Scholar 

  57. Mahshid B et al (2018) Lipid peroxidation and its role in the expression of NLRP1a and NLRP3 genes in testicular tissue of male rats: a model of spinal cord injury

  58. Mancuso P, Raman S, Glynn A, Barry F, Murphy JM (2019) Mesenchymal stem cell therapy for osteoarthritis. The critical role of the cell secretome. Front Bioeng Biotechnol 7:9. https://doi.org/10.3389/fbioe.2019.00009

    Article  PubMed  PubMed Central  Google Scholar 

  59. Matas J et al (2019) Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial . Stem Cells Transl Med 8:215–224

    CAS  PubMed  Article  Google Scholar 

  60. Miyaki S, Asahara H (2012) Macro view of microRNA function in osteoarthritis. Nat Rev Rheumatol 8:543–552. https://doi.org/10.1038/nrrheum.2012.128

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Miyaki S, Lotz MK (2018) Extracellular vesicles in cartilage homeostasis and osteoarthritis. Curr Opin Rheumatol 30:129–135. https://doi.org/10.1097/BOR.0000000000000454

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Miyaki S et al (2010) MicroRNA-140 plays dual roles in both cartilage development and homeostasis. Genes Dev 24:1173–1185. https://doi.org/10.1101/gad.1915510

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Mohammadinejad R et al (2020) Nanotechnological strategies for osteoarthritis diagnosis, monitoring, clinical management, and regenerative medicine: recent advances and future opportunities. Curr Rheumatol Rep 22:12. https://doi.org/10.1007/s11926-020-0884-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. Mohammed I et al (2020) Subventricular zone-derived extracellular vesicles promote functional recovery in rat model of spinal cord injury by inhibition of NLRP3 inflammasome complex formation. Metab Brain Dis 35:809

    CAS  PubMed  Article  Google Scholar 

  65. Morales-Ivorra I, Romera-Baures M, Roman-Viñas B, Serra-Majem L (2018) Osteoarthritis and the Mediterranean diet: a systematic review. Nutrients 10:1030

    PubMed Central  Article  CAS  Google Scholar 

  66. Mustonen A-M, Nieminen P (2021) Extracellular vesicles and their potential significance in the pathogenesis and treatment of osteoarthritis. Pharmaceuticals 14:315

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Nakamura Y et al (2015) Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration. FEBS Lett 589:1257–1265. https://doi.org/10.1016/j.febslet.2015.03.031

    CAS  Article  PubMed  Google Scholar 

  68. Natasha G, Gundogan B, Tan A, Farhatnia Y, Wu W, Rajadas J, Seifalian AM (2014) Exosomes as immunotheranostic nanoparticles. Clin Ther 36:820–829. https://doi.org/10.1016/j.clinthera.2014.04.019

    CAS  Article  PubMed  Google Scholar 

  69. Nikmehr B et al (2017) The correlation of gene expression of inflammasome indicators and impaired fertility in rat model of spinal cord injury: a time course study. Urol J 14:5057–5063

    PubMed  Google Scholar 

  70. Noori L, Arabzadeh S, Mohamadi Y, Mojaverrostami S, Mokhtari T, Akbari M, Hassanzadeh G (2020) Intrathecal administration of the extracellular vesicles derived from human Wharton’s jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats. Neurosci Res 170:87

    PubMed  Article  CAS  Google Scholar 

  71. Pal B, Endisha H, Zhang Y, Kapoor M (2015) mTOR: a potential therapeutic target in osteoarthritis? Drugs R D 15:27–36

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Palazzo C, Nguyen C, Lefevre-Colau M-M, Rannou F, Poiraudeau S (2016) Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med 59:134–138. https://doi.org/10.1016/j.rehab.2016.01.006

    Article  PubMed  Google Scholar 

  73. Pas HI, Winters M, Haisma HJ, Koenis MJ, Tol JL, Moen MH (2017) Stem cell injections in knee osteoarthritis: a systematic review of the literature. Br J Sports Med 51:1125–1133

    PubMed  Article  Google Scholar 

  74. Pham T, Cornea A, Jenkins A, Blick KE, Scofield RH (2007) Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 333:333–339

    PubMed  Article  Google Scholar 

  75. Phinney DG, Pittenger MF (2017) Concise review: MSC-derived exosomes for cell‐free therapy. Stem Cells 35:851–858

    CAS  PubMed  Article  Google Scholar 

  76. Qi H, Liu DP, Xiao DW, Tian DC, Su YW, Jin SF (2019) Exosomes derived from mesenchymal stem cells inhibit mitochondrial dysfunction-induced apoptosis of chondrocytes via p38, ERK, and Akt pathways . In Vitro Cell Dev Biol Anim 55:203–210. https://doi.org/10.1007/s11626-019-00330-x

    CAS  Article  PubMed  Google Scholar 

  77. Raeissadat SA, Gharooee Ahangar A, Rayegani SM, Minator Sajjadi M, Ebrahimpour A, Yavari P (2020) Platelet-rich plasma-derived growth factor vs hyaluronic acid injection in the individuals with knee osteoarthritis: a one year randomized clinical trial. J Pain Res 13:1699–1711. https://doi.org/10.2147/JPR.S210715

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Ragni E et al (2019) miR-22-5p and miR-29a-5p are reliable reference genes for analyzing extracellular vesicle-associated miRNAs in adipose-derived mesenchymal stem cells and are stable under inflammatory priming mimicking osteoarthritis condition. Stem Cell Rev Rep 15:743–754. https://doi.org/10.1007/s12015-019-09899-y

    CAS  Article  PubMed  Google Scholar 

  79. Ramasubramanian L, Kumar P, Wang A (2020) Engineering extracellular vesicles as nanotherapeutics for regenerative medicine. Biomolecules 10:48

    CAS  Article  Google Scholar 

  80. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, Sokolove J (2016) Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol 12:580–592. https://doi.org/10.1038/nrrheum.2016.136

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Sajjadi MM, Keyhani S, Kazemi SM, Hanafizadeh B, Ebrahimpour A, Banasiri M (2019) Patient satisfaction following total knee arthroplasty: comparison of short-term results in rheumatoid arthritis and osteoarthritis. Arch Bone Joint Surg 7:61

    Google Scholar 

  82. Scotti C et al (2016) Cartilage repair in the inflamed joint: considerations for biological augmentation toward tissue regeneration. Tissue Eng Part B 22:149–159

    CAS  Article  Google Scholar 

  83. Shah SS, Mithoefer K (2020) Current applications of growth factors for knee cartilage repair and osteoarthritis treatment. Curr Rev Musculoskel Med 13:641

    Article  Google Scholar 

  84. Smith SR, Deshpande BR, Collins JE, Katz JN, Losina E (2016) Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review. Osteoarthr Cartil 24:962–972. https://doi.org/10.1016/j.joca.2016.01.135

    CAS  Article  Google Scholar 

  85. Sokolove J, Lepus CM (2013) Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Therap Adv Musculoskelet Dis 5:77–94

    CAS  Article  Google Scholar 

  86. Spiller KL, Anfang RR, Spiller KJ, Ng J, Nakazawa KR, Daulton JW, Vunjak-Novakovic G (2014) The role of macrophage phenotype in vascularization of tissue engineering scaffolds. Biomaterials 35:4477–4488

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Stamenkovic I (2003) Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 200:448–464

    CAS  PubMed  Article  Google Scholar 

  88. Subra C, Laulagnier K, Perret B, Record M (2007) Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 89:205–212

    CAS  PubMed  Article  Google Scholar 

  89. Sun AR, Friis T, Sekar S, Crawford R, Xiao Y, Prasadam I (2016) Is synovial macrophage activation the inflammatory link between obesity and osteoarthritis? Curr Rheumatol Rep 18:1–14

    Article  CAS  Google Scholar 

  90. Sun X, Meng H, Wan W, Xie M, Wen C (2019) Application potential of stem/progenitor cell-derived extracellular vesicles in renal diseases. Stem Cell Res Ther 10:1–9

    Article  CAS  Google Scholar 

  91. Tao SC, Yuan T, Zhang YL, Yin WJ, Guo SC, Zhang CQ (2017) Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model . Theranostics 7:180–195. https://doi.org/10.7150/thno.17133

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Timmers L et al (2008) Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 1:129–137

    Article  CAS  Google Scholar 

  93. Tkach M, Théry C (2016) Communication by extracellular vesicles: where we are and where we need to go. Cell 164:1226–1232. https://doi.org/10.1016/j.cell.2016.01.043

    CAS  Article  PubMed  Google Scholar 

  94. Tofiño-Vian M, Guillén MI, Pérez D, Caz MD, Castejón MA, Alcaraz MJ (2017) Extracellular vesicles from adipose-derived mesenchymal stem cells downregulate senescence features in osteoarthritic osteoblasts. Oxid Med Cell Longev 2017:7197598. https://doi.org/10.1155/2017/7197598

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Tofiño-Vian M, Guillén MI, Pérez D, Caz MD, Silvestre A, Alcaraz MJ (2018) Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell Physiol Biochem 47:11–25. https://doi.org/10.1159/000489739

    CAS  Article  PubMed  Google Scholar 

  96. Toh WS, Foldager CB, Pei M, Hui JH (2014) Advances in mesenchymal stem cell-based strategies for cartilage repair and regeneration Stem. Cell Rev Rep 10:686–696. https://doi.org/10.1007/s12015-014-9526-z

    CAS  Article  Google Scholar 

  97. Toh WS, Lai RC, Hui JHP, Lim SK (2017) MSC exosome as a cell-free MSC therapy for cartilage regeneration: implications for osteoarthritis treatment Semin. Cell Dev Biol 67:56–64. https://doi.org/10.1016/j.semcdb.2016.11.008

    CAS  Article  Google Scholar 

  98. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659. https://doi.org/10.1038/ncb1596

    CAS  Article  PubMed  Google Scholar 

  99. van den Berg WB (1999) The role of cytokines and growth factors in cartilage destruction in osteoarthritis and rheumatoid arthritis. Zeitschrift für Rheumatologie 58:136–141. https://doi.org/10.1007/s003930050163

    Article  PubMed  Google Scholar 

  100. Verma P, Dalal K (2011) ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem 112:3507–3514. https://doi.org/10.1002/jcb.23298

    CAS  Article  PubMed  Google Scholar 

  101. Vincent TL (2019) IL-1 in osteoarthritis: time for a critical review of the literature F1000Res 8:F1000 Faculty Rev-1934 https://doi.org/10.12688/f1000research.18831.1

  102. Wang J, Xia J, Huang R, Hu Y, Fan J, Shu Q, Xu J (2020) Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization. Stem Cell Res Therapy 11:424. https://doi.org/10.1186/s13287-020-01937-8

    CAS  Article  Google Scholar 

  103. Wang J, Xia J, Huang R, Hu Y, Fan J, Shu Q, Xu J (2020) Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization. Stem Cell Res Ther 11:1–12

    Article  CAS  Google Scholar 

  104. Withrow J, Murphy C, Liu Y, Hunter M, Fulzele S, Hamrick MW (2016) Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res Therapy 18:286. https://doi.org/10.1186/s13075-016-1178-8

    CAS  Article  Google Scholar 

  105. Witwer KW et al (2019) Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles 8:1609206

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat Inflamm 2014:561459. https://doi.org/10.1155/2014/561459

    CAS  Article  Google Scholar 

  107. Wolf P (1967) The nature and significance of platelet products in human plasma. Br J Haematol 13:269–288. https://doi.org/10.1111/j.1365-2141.1967.tb08741.x

    CAS  Article  PubMed  Google Scholar 

  108. Worthington EN, Hagood JS (2020) Therapeutic use of extracellular vesicles for acute and chronic lung disease. Int J Mol Sci 21:2318

    CAS  PubMed Central  Article  Google Scholar 

  109. Wu J et al (2019) miR-100-5p-abundant exosomes derived from infrapatellar fat pad MSCs protect articular cartilage and ameliorate gait abnormalities via inhibition of mTOR in osteoarthritis. Biomaterials 206:87–100. https://doi.org/10.1016/j.biomaterials.2019.03.022

    CAS  Article  PubMed  Google Scholar 

  110. Wu Y et al (2015) Mesenchymal stem cells suppress fibroblast proliferation and reduce skin fibrosis through a TGF-β3-dependent activation. Int J Low Extrem Wounds 14:50–62. https://doi.org/10.1177/1534734614568373

    CAS  Article  PubMed  Google Scholar 

  111. Wu X, Wang Y, Xiao Y, Crawford R, Mao X, Prasadam I (2020) Extracellular vesicles: potential role in osteoarthritis regenerative medicine. J Orthop Transl 21:73–80. https://doi.org/10.1016/j.jot.2019.10.012

    CAS  Article  Google Scholar 

  112. Wyles CC, Houdek MT, Behfar A, Sierra RJ (2015) Mesenchymal stem cell therapy for osteoarthritis: current perspectives. Stem Cells Cloning 8:117–124. https://doi.org/10.2147/sccaa.S68073

    Article  PubMed  PubMed Central  Google Scholar 

  113. Xie Y, Zhou W, Zhong Z, Zhao Z, Yu H, Huang Y, Zhang P (2020) Metabolic syndrome, hypertension, and hyperglycemia were positively associated with knee osteoarthritis, while dyslipidemia showed no association with knee osteoarthritis. Clin Rheumatol 1–14

  114. Yang Y, Wang H, Kouadir M, Song H, Shi F (2019) Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death Dis 10:128. https://doi.org/10.1038/s41419-019-1413-8

    Article  PubMed  PubMed Central  Google Scholar 

  115. Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, Lim SK (2013) Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev 65:336–341. https://doi.org/10.1016/j.addr.2012.07.001

    CAS  Article  PubMed  Google Scholar 

  116. Yoshimura N, Muraki S, Oka H, Kawaguchi H, Nakamura K, Akune T (2011) Association of knee osteoarthritis with the accumulation of metabolic risk factors such as overweight, hypertension, dyslipidemia, and impaired glucose tolerance in Japanese men and women: the ROAD study. J Rheumatol 38:921–930

    PubMed  Article  Google Scholar 

  117. Yubo M, Yanyan L, Li L, Tao S, Bo L, Lin C (2017) Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: A meta-analysis. PLoS ONE 12:e0175449. https://doi.org/10.1371/journal.pone.0175449

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. Yusuf E (2016) Pharmacologic and non-pharmacologic treatment of osteoarthritis. Curr Treat Options Rheumatol 2:111–125. https://doi.org/10.1007/s40674-016-0042-y

    Article  Google Scholar 

  119. Zhang Y, Jordan JM (2010) Epidemiology of osteoarthritis. Clin Geriatr Med 26:355–369. https://doi.org/10.1016/j.cger.2010.03.001

    Article  PubMed  PubMed Central  Google Scholar 

  120. Zhang S, Chu WC, Lai RC, Lim SK, Hui JH, Toh WS (2016) Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthr Cartil 24:2135–2140. https://doi.org/10.1016/j.joca.2016.06.022

    CAS  Article  Google Scholar 

  121. Zhang S, Teo KYW, Chuah SJ, Lai RC, Lim SK, Toh WS (2019) MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials 200:35–47. https://doi.org/10.1016/j.biomaterials.2019.02.006

    CAS  Article  PubMed  Google Scholar 

  122. Zhu Y et al (2017) Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis Stem. Cell Res Ther 8:64. https://doi.org/10.1186/s13287-017-0510-9

    CAS  Article  Google Scholar 

  123. Zhuang X et al (2011) Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther 19:1769–1779. https://doi.org/10.1038/mt.2011.164

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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SJS1 and AM conceived of the presented idea. SJS1, SMH, MMS and SJS2 equally participated in drafting the article. MMS and AM participated in revising it critically for important intellectual content. All authors gave final approval of the version to be submitted and any revised version.

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Correspondence to Arash Maleki.

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Jousheghan, S.S., Sajjadi, M.M., Jousheghan, S.S. et al. Extracellular vesicles as novel approaches for the treatment of osteoarthritis: a narrative review on potential mechanisms. J Mol Histol 52, 879–891 (2021). https://doi.org/10.1007/s10735-021-10017-x

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Keywords

  • Osteoarthritis
  • Inflammation
  • Cartilage
  • Regeneration
  • Extracellular vehicles
  • Stem cell