Exosomes of stem cells: a potential frontier in the treatment of osteoarthritis

Abstract

The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.

Keywords

osteoarthritis / cartilage / exosomes / stem cells / regenerative medicine

Acknowledgements

This project was supported by the National Natural Science Foundation of China (Grant No. 82302758), China Postdoctoral Science Foundation (Grant No. 2023M731419), the Jiangsu Funding Program for Excellent Postdoctoral Talent (Grant No. 2022ZB896), and the Yangzhou Key Laboratory of Orthopedics (Grant No. YZ2023249). We have obtained the relevant permissions for BioRender (www.biorender.com) and have used the correct permission text as required by the copyright holders.

Author contributions

Xiaofei Wang (Writing—original draft), Lei Xu (Data curation), Zhimin Wu (Data curation), Linbing Lou (Data curation), Cunyi Xia (Data curation), Haixiang Miao (Data curation), Jihang Dai (Writing—original draft, Writing—review & editing), Wenyong Fei (Conceptualization, Investigation) and Jingcheng Wang (Conceptualization, Resources, Supervision).

Conflict of interest

None declared.

References

[1] Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. The Lancet 2019;393:1745-59. https://doi.org/10.1016/S0140-6736(19)30417-9.

[2] Yue L, Berman J. What is osteoarthritis?. JAMA 2022;327:1300. https://doi.org/10.1001/jama.2022.1980.

[3] Martel-Pelletier J, Barr AJ, Cicuttini FM et al. Osteoarthritis. Nat Rev Dis Primers 2016;2:16072. https://doi.org/10.1038/nrdp.2016.72.

[4] Lane N, Felson D. A promising treatment for osteoarthritis?. Ann Intern Med 2020;173:580-1. https://doi.org/10.7326/M20-4938.

[5] Zhao X, Shah D, Gandhi K et al. Clinical, humanistic, and economic burden of osteoarthritis among noninstitutionalized adults in the United States. Osteoarthritis Cartilage 2019;27:1618-26. https://doi.org/10.1016/j.joca.2019.07.002.

[6] Largo R, Herrero-Beaumont G. Joint obesity as a pathogenic factor in osteoarthritis. Osteoarthritis Cartilage 2021;29:1239-41. https://doi.org/10.1016/j.joca.2021.05.062.

[7] Wang XF, Ma ZH, Teng XR. Isokinetic strength test of muscle strength and motor function in total knee arthroplasty. Orthopaedic Surgery 2020;12:878-89. https://doi.org/10.1111/os.12699.

[8] Kloppenburg M. Inflammation is a relevant treatment target in osteoarthritis. The Lancet 2023;402:1725-6. https://doi.org/10.1016/S0140-6736(23)01726-9.

[9] Hodgkinson T, Kelly DC, Curtin CM et al. Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat Rev Rheumatol 2022;18:67-84. https://doi.org/10.1038/s41584-021-00724-w.

[10] Wei Y, Luo L, Gui T et al. Targeting cartilage EGFR pathway for osteoarthritis treatment. Sci Transl Med 2021;13:eabb3946. https://doi.org/10.1126/scitranslmed.abb3946.

[11] Garcia-Martin R, Wang G, Brandão BB et al. MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature 2022;601:446-51. https://doi.org/10.1038/s41586-021-04234-3.

[12] Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science 2020;367:eaau6977. https://doi.org/10.1126/science.aau6977.

[13] Zheng R, Zhang K, Tan S et al. Exosomal circLPAR1 functions in colorectal cancer diagnosis and tumorigenesis through suppressing BRD 4 via METTL3-eIF3h interaction. Mol Cancer 2022;21:49. https://doi.org/10.1186/s12943-021-01471-y.

[14] Cao Y, Wang Z, Yan Y et al. Enterotoxigenic bacteroidesfragilis promotes intestinal inflammation and malignancy by inhibiting exosome-packaged miR-149-3p. Gastroenterology 2021;161:1552-66. https://doi.org/10.1053/j.gastro.2021.08.003.

[15] Sahoo S, Adamiak M, Mathiyalagan P et al. Therapeutic and diagnostic translation of extracellular vesicles in cardiovascular diseases: roadmap to the clinic. Circulation 2021;143:1426-49. https://doi.org/10.1161/CIRCULATIONAHA.120.049254.

[16] Jin S, Wang Y, Wu X et al. Young exosome bio-nanoparticles restore aging-impaired tendon stem/progenitor cell function and reparative capacity. Adu Mater 2023;35:e2211602. https://doi.org/10.1002/adma. 202211602.

[17] Jeppesen DK, Fenix AM, Franklin JL et al. Reassessment of exosome composition. Cell 2019;177:428-45. https://doi.org/10.1016/j.cell.2019.02.029.

[18] Murphy C, Withrow J, Hunter M et al. Emerging role of extracellular vesicles in musculoskeletal diseases. Mol Aspects Med 2018;60:123-8. https://doi.org/10.1016/j.mam.2017.09.006.

[19] Wu Y, Li J, Zeng Y et al. Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies. Int J Oral Sci 2022;14:40. https://doi.org/10.1038/s41368-022-00187-z.

[20] Ni Z, Zhou S, Li S et al. Exosomes: roles and therapeutic potential in osteoarthritis. Bone Res 2020;8:25. https://doi.org/10.1038/s41413-020-0100-9.

[21] Zhou QF, Cai YZ, Lin XJ. The dual character of exosomes in osteoarthritis: antagonists and therapeutic agents. Acta Biomater 2020;105:15-25. https://doi.org/10.1016/j.actbio.2020.01.040.

[22] Loeser RF, Collins JA, Diekman BO. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol 2016;12:412-20. https://doi.org/10.1038/nrrheum.2016.65.

[23] Berenbaum F, Wallace II, Lieberman DE et al. Modern-day environmental factors in the pathogenesis of osteoarthritis. Nat Rev Rheumatol 2018;14:674-81. https://doi.org/10.1038/s41584-018-0073-х.

[24] Rezuş E, Burlui A, Cardoneanu A et al. From pathogenesis to therapy in knee osteoarthritis: bench-to-bedside. Int J Mol Sci 2021;22:2697. https://doi.org/10.3390/ijms22052697.

[25] Rahmati M, Nalesso G, Mobasheri A et al. Aging and osteoarthritis: Central role of the extracellular matrix. Ageing Res Rev 2017;40:20-30. https://doi.org/10.1016/j.arr.2017.07.004.

[26] Luo Y, Sinkeviciute D, He Y et al. The minor collagens in articular cartilage. Protein Cell 2017;8:560-72. https://doi.org/10.1007/s13238-017-0377-7.

[27] Zhang CH, Gao Y, Hung HH et al. Creb 5 coordinates synovial joint formation with the genesis of articular cartilage. Nat Commun 2022;13:7295. https://doi.org/10.1038/s41467-022-35010-0.

[28] Chen D, Shen J, Zhao W et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res 2017;5:16044. https://doi.org/10.1038/boneres.2016.44.

[29] Del Sordo L, Blackler GB, Philpott HT et al. Impaired efferocytosis by synovial macrophages in patients with knee osteoarthritis. Arthritis & Rheumatology 2023;75:685-96. https://doi.org/10.1002/art.42412.

[30] Sanchez-Lopez E, Coras R, Torres A et al. Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol 2022;18:258-75. https://doi.org/10.1038/s41584-022-00749-9.

[31] Asghar S, Litherland GJ, Lockhart JC et al. Exosomes in intercellular communication and implications for osteoarthritis. Rheumatology (Oxford) 2020;59:57-68. https://doi.org/10.1093/rheumatology/kez462.

[32] Sohn DH, Sokolove J, Sharpe O et al. Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4. Arthritis Res Ther 2012;14:R7. https://doi.org/10.1186/ar3555.

[33] Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage 2015;23:1825-34. https://doi.org/10.1016/j.joca.2015.08.015.

[34] Loeser RF, Goldring SR, Scanzello CR et al. Osteoarthritis: a disease of the joint as an organ. Arthritis & Rheumatism 2012;64:1697-707. https://doi.org/10.1002/art.34453.

[35] Katz JN, Arant KR, Loeser RF. Diagnosis and treatment of hip and knee osteoarthritis: A review. JAMA 2021;325:568-78. https://doi.org/10.1001/jama.2020.22171.

[36] Li Y, Huang P, Nasser MI et al. Role of exosomes in bone and joint disease metabolism, diagnosis, and therapy. EurJ Pharm Sci 2022;176:106262. https://doi.org/10.1016/j.ejps.2022.106262.

[37] Wu C, He Y, Yao Y et al. Exosomes treating osteoarthritis: hope with challenge. Heliyon 2023;9:e13152. https://doi.org/10.1016/j.heliyon.2023.e13152.

[38] Zhou Q, Cai Y, Jiang Y et al. Exosomes in osteoarthritis and cartilage injury: advanced development and potential therapeutic strategies. Int. J. Biol. Sci. 2020; 16:1811-20. https://doi.org/10.7150/ijbs.41637.

[39] Mathieu M, Martin-Jaular L, Lavieu G et al. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol 2019;21:9-17. https://doi.org/10.1038/s41556-018-0250-9.

[40] CHARGAFF E, WEST R. The biological significance of the thromboplastic protein of blood. J Biol Chem 1946;166:189-97.

[41] Couch Y, Buzàs EI,Di Vizio D et al. A brief history of nearly EV-erything-the rise and rise of extracellular vesicles. J Extracellular Vesicle 2021;10:e12144. https://doi.org/10.1002/jev2.12144.

[42] Fox AS, Duggleby WF, Gelbart WM, et al. DNA-induced transformation in Drosophila: evidence for transmission without integration. Proc Natl Acad Sci USA 1970;67:1834-8. https://doi.org/10.1073/pnas.67.4.1834.

[43] Fox AS, Yoon SB. DNA-induced transformation in Drosophila: locus-specificity and the establishment of transformed stocks. Proc Natl Acad Sci USA 1970;67:1608-15. https://doi.org/10.1073/pnas.67.3.1608.

[44] Fox AS, Yoon SB, Gelbart WM. DNA-induced transformation in Drosophila: genetic analysis of transformed stocks. Proc Natl Acad Sci USA 1971;68:342-6. https://doi.org/10.1073/pnas.68.2.342.

[45] Mishra NC, Tatum EL. Non-Mendelian inheritance of DNAinduced inositol independence in Neurospora. Proc Natl Acad Sci USA 1973;70:3875-9. https://doi.org/10.1073/pnas.70.12.3875.

[46] Witwer KW, Théry C. Extracellular vesicles or exosomes? On primacy, precision, and popularity influencing a choice of nomenclature. J of Extracellular Vesicle 2019;8:1648167. https://doi.org/10.1080/20013078.2019.1648167.

[47] Johnstone RM, Adam M, Hammond JR et al. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 1987;262:9412-20. https://doi.org/10.1016/S0021-9258(18)48095-7.

[48] Johnstone RM, Bianchini A, Teng K. Reticulocyte maturation and exosome release: transferrin receptor containing exosomes shows multiple plasma membrane functions. Blood 1989;74:1844-51. https://doi.org/10.1182/blood.V74.5.1844.1844.

[49] Raposo G, Nijman HW, Stoorvogel W et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161-72. https://doi.org/10.1084/jem.183.3.1161.

[50] Liu Y, Wang Y, Lv Q et al. Exosomes: from garbage bins to translational medicine. Int J Pharm 2020;583:119333. https://doi.org/10.1016/j.ijpharm.2020.119333.

[51] Nikfarjam S, Rezaie J, Zolbanin NM et al. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med 2020;18:449. https://doi.org/10.1186/s129 67-020-02622-3.

[52] Wu R, Li H, Sun C et al. Exosome-based strategy for degenerative disease in orthopedics: recent progress and perspectives. Journal of Orthopaedic Translation 2022;36:8-17. https://doi.org/10.1016/j.jot.2022.05.009.

[53] Théry C, Witwer KW, Aikawa E et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines J of Extracellular Vesicle 2018;7:1535750. https://doi.org/10.1080/20013078.2018.1535750.

[54] Pluchino S, Smith JA. Explicating exosomes: reclassifying the rising stars of intercellular communication. Cell 2019;177:2257. https://doi.org/10.1016/j.cell.2019.03.020.

[55] Ostrowski M, Carmo NB, Krumeich S et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 2010;12:19-30. https://doi.org/10.1038/ncb2000.

[56] Withrow J, Murphy C, Liu Y et al. Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2016;18:286. https://doi.org/10.1186/s13075-016-1178-8.

[57] Bjørge IM, Kim SY, Mano JF et al. Extracellular vesicles, exosomes and shedding vesicles in regenerative medicine-a new paradigm for tissue repair. Biomater. Sci. 2017; 6:60-78. https://doi.org/10.1039/C7BM00479F.

[58] Brown L, Wolf JM, Prados-Rosales R et al. Through the wall: extracellular vesicles in gram-positive bacteria, mycobacteria and fungi. Nat Rev Micro 2015;13:620-30. https://doi.org/10.1038/nrmicro3480.

[59] An Q, van Bel AJ, Hückelhoven R. Do plant cells secrete exosomes derived from multivesicular bodies?. Plant Signal Behav 2007;2:4-7. https://doi.org/10.4161/psb.2.1.3596.

[60] Man F, Wang J, Lu R. Techniques and applications of animaland plant-derived exosome-based drug delivery system. J Biomed Nanotechnol 2020;16:1543-69. https://doi.org/10.1166/jbn.2020.2993.

[61] Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014;30:255-89. https://doi.org/10.1146/annurev-cellbio-101512-122326.

[62] Yang XX, Sun C, Wang L et al. New insight into isolation, identification techniques and medical applications of exosomes. J Controlled Release 2019;308:119-29. https://doi.org/10.1016/j.jconre1.2019.07.021.

[63] Yang D, Zhang W, Zhang H et al. Progress, opportunity, and perspective on exosome isolation-efforts for efficient exosomebased theranostics. Theranostics 2020;10:3684-707. https://doi.org/10.7150/thno.41580.

[64] Cao F, Gao Y, Chu Q et al. Proteomics comparison of exosomes from serum and plasma between ultracentrifugation and polymer-based precipitation kit methods. Electrophoresis 2019;40:3092-8. https://doi.org/10.1002/elps.201900295.

[65] Sidhom K, Obi PO, Saleem A. A review of exosomal isolation methods: is size exclusion chromatography the best option? Int J Mol Sci 2020;21:6466. https://doi.org/10.3390/ijms21186466.

[66] Tran PHL, Wang T, Yin W et al. Development of a nanoamorphous exosomal delivery system as an effective biological platform for improved encapsulation of hydrophobic drugs. Int J Pharm 2019;566:697-707. https://doi.org/10.1016/j.ijpharm.2019.06.028.

[67] Muller L, Hong CS, Stolz DB et al. Isolation of biologically-active exosomes from human plasma. J Immunol Methods 2014;411:5565. https://doi.org/10.1016/j.jim.2014.06.007.

[68] Mi B, Chen L, Xiong Y et al. Saliva exosomes-derived UBE2O mRNA promotes angiogenesis in cutaneous wounds by targeting SMAD6. J Nanobiotechnol 2020;18:68. https://doi.org/10.1186/s12951-020-00624-3.

[69] Hiemstra TF, Charles PD, Gracia T et al. Human urinary exosomes as innate immune effectors. J Am Soc Nephrol 2014;25:2017-27. https://doi.org/10.1681/ASN.2013101066.

[70] Xu H, Li M, Pan Z et al. miR-3184-3p enriched in cerebrospinal fluid exosomes contributes to progression of glioma and promotes M2-like macrophage polarization. Cancer Sci 2022;113:2668-80. https://doi.org/10.1111/cas.15372.

[71] Xu WM, Li A, Chen JJ et al. Research development on exosome separation technology. J Membrane Biol 2023;256:25-34. https://doi.org/10.1007/s00232-022-00260-y.

[72] Wu Y, Deng W, Klinke DJ, 2nd. Exosomes: improved methods to characterize their morphology, RNA content, and surface protein biomarkers. Analyst 2015;140:6631-42. https://doi.org/10.1039/C5AN00688K.

[73] Dragovic RA, Gardiner C, Brooks AS et al. Sizing and phenotyping of cellular vesicles using nanoparticle tracking Analysis. Nanomed Nanotechnol Biol Med 2011;7:780-8. https://doi.org/10.1016/j.nano.2011.04.003.

[74] Witwer KW, Buzás EI, Bemis LT et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracellular Vesicle 2013;2: 20360. https://doi.org/10.3402/jev.v2i0.20360.

[75] Gercel-Taylor C, Atay S, Tullis RH et al. Nanoparticle analysis of circulating cell-derived vesicles in ovarian cancer patients. Anal Biochem 2012;428:44-53. https://doi.org/10.1016/j.ab.2012.06.004.

[76] Qazi REM, Sajid Z, Zhao C et al. Lyophilization based isolation of exosomes. Int J Mol Sci 2023;24:10477. https://doi.org/10.3390/ijms241310477.

[77] Chen J, Chen J, Cheng Y et al. Mesenchymal stem cell-derived exosomes protect beta cells against hypoxia-induced apoptosis via miR-21 by alleviating ER stress and inhibiting p 38 MAPK phosphorylation. Stem Cell Res Ther 2020;11:97. https://doi.org/10.1186/s13287-020-01610-0.

[78] Gurunathan S, Kang MH, Jeyaraj M et al. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes. Cells 2019;8:307. https://doi.org/10.3390/cells8040307.

[79] Kloppenburg M, Berenbaum F. Osteoarthritis year in review 2019: epidemiology and therapy. Osteoarthritis Cartilage, 2020; 28:242-8. https://doi.org/10.1016/j.joca.2020.01.002.

[80] Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat Rev Rheumatol 2012;8:390-8. https://doi.org/10.1038/nrrheum.2012.80.

[81] Wei G, Lu K, Umar M et al. Risk of metabolic abnormalities in osteoarthritis: a new perspective to understand its pathological mechanisms. Bone Res 2023;11:63. https://doi.org/10.1038/s41413-023-00301-9.

[82] Sandhu A, Rockel JS, Lively S et al. Emerging molecular biomarkers in osteoarthritis pathology. Therapeutic Advances in Musculoskeletal 2023;15:1759720X231177116. https://doi.org/10.1177/1759720X231177116.

[83] Fan WJ, Liu D, Pan LY et al. Exosomes in osteoarthritis: updated insights on pathogenesis, diagnosis, and treatment. Front Cell Dev Biol 2022;10:949690. https://doi.org/10.3389/fcell.2022.949690.

[84] de Lange-Brokaar BJ, Ioan-Facsinay A, van Osch GJ et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 2012;20:1484-99. https://doi.org/10.1016/j.joca.2012.08.027.

[85] Han D, Fang Y, Tan X et al. The emerging role of fibroblast-like synoviocytes-mediated synovitis in osteoarthritis: an update. J Cellular Molecular Medi 2020;24:9518-32. https://doi.org/10.1111/jcmm.15669.

[86] Griffin TM, Scanzello CR. Innate inflammation and synovial macrophages in osteoarthritis pathophysiology. Clin Exp Rheumatol 2019; 37 (Suppl 120): 57-63.

[87] Lepetsos P, Papavassiliou KA, Papavassiliou AG. Redox and NF κb signaling in osteoarthritis. Free Radical Biol Med 2019;132:90100. https://doi.org/10.1016/j.freeradbiomed.2018.09.025.

[88] Brandl A, Hartmann A, Bechmann V et al. Oxidative stress induces senescence in chondrocytes. Journal Orthopaedic Research 2011;29:1114-20. https://doi.org/10.1002/jor.21348.

[89] Yu H, Ye WB, Zhong ZM et al. Effect of advanced oxidation protein products on articular cartilage and synovium in a rabbit osteoarthritis model. Orthopaedic Surgery 2015;7:161-7. https://doi.org/10.1111/os.12179.

[90] Kapoor M, Martel-Pelletier J, Lajeunesse D et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 2011;7:33-42. https://doi.org/10.1038/nrrheum.2010.196.

[91] Domenis R, Zanutel R, Caponnetto F et al. Characterization of the proinflammatory profile of synovial fluid-derived exosomes of patients with osteoarthritis. Mediators Inflamm 2017;2017:1. https://doi.org/10.1155/2017/4814987.

[92] Kim M, Shin DI, Choi BH et al. Exosomes from IL-1β-primed mesenchymal stem cells inhibited IL-1β-and TNF-α-mediated inflammatory responses in osteoarthritic SW 982 cells. Tissue Eng Regen Med 2021;18:525-36. https://doi.org/10.1007/s13770-020-00324-x.

[93] Qiu M, Liu D, Fu Q. MiR-129-5p shuttled by human synovial mesenchymal stem cell-derived exosomes relieves IL-1β induced osteoarthritis via targeting HMGB1. Life Sci 2021;269:118987. https://doi.org/10.1016/j.lfs.2020.118987.

[94] Chang LH, Wu SC, Chen CH et al. Exosomes derived from hypoxia-cultured Human adipose stem cells alleviate articular chondrocyte inflammaging and post-traumatic osteoarthritis progression. Int J Mol Sci 2023;24:13414. https://doi.org/10.3390/ijms241713414.

[95] Jin Z, Ren J, Qi S. Exosomal miR-9-5p secreted by bone marrowderived mesenchymal stem cells alleviates osteoarthritis by inhibiting syndecan-1. Cell Tissue Res 2020;381:99-114. https://doi.org/10.1007/s00441-020-03193-x.

[96] Zhou Y, Ming J, Li Y et al. Exosomes derived from miR-126-3poverexpressing synovial fibroblasts suppress chondrocyte inflammation and cartilage degradation in a rat model of osteoarthritis. Cell Death Discov. 2021;7:37. https://doi.org/10.1038/s41420-021-00418-y.

[97] Lai CC, Liao B, Peng S et al. Synovial fibroblast-miR-214-3p-derived exosomes inhibit inflammation and degeneration of cartilage tissues of osteoarthritis rats. Mol Cell Biochem 2023;478:637-49. https://doi.org/10.1007/s11010-022-04535-9.

[98] Zheng T, Li Y, Zhang X et al. Exosomes derived from miR-212-5p overexpressed Human synovial mesenchymal stem cells suppress chondrocyte degeneration and inflammation by targeting ELF3. Front Bioeng Biotechnol 2022;10:816209. https://doi.org/10.3389/fbioe.2022.816209.

[99] Theocharis AD, Skandalis SS, Gialeli C et al. Extracellular matrix structure. Adv Drug Deliv Rev 2016;97:4-27. https://doi.org/10.1016/j.addr.2015.11.001.

[100] Peng Z, Sun H, Bunpetch V et al. The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials 2021;268:120555. https://doi.org/10.1016/j.biomaterials.2020.120555.

[101] Huang S, Liu Y, Wang C et al. Strategies for cartilage repair in osteoarthritis based on diverse mesenchymal stem cells-derived extracellular vesicles. Orthopaedic Surgery 2023;15:2749-65. https://doi.org/10.1111/os.13848.

[102] Xia Q,Wang Q Lin F et al. miR-125a-5p-abundant exosomes derived from mesenchymal stem cells suppress chondrocyte degeneration via targeting E2F2 in traumatic osteoarthritis. Bioengineered 2021;12:11225-38. https://doi.org/10.1080/21655979.2021.1995580.

[103] Wang Y, Yu D, Liu Z et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther 2017;8:189. https://doi.org/10.1186/s13287-017-0632-0.

[104] Wang Z, Yan K, Ge G et al. Exosomes derived from miR-155-5p-overexpressing synovial mesenchymal stem cells prevent osteoarthritis via enhancing proliferation and migration, attenuating apoptosis, and modulating extracellular matrix secretion in chondrocytes. Cell Biol Toxicol 2021;37:85-96. https://doi.org/10.1007/s10565-020-09559-9.

[105] Tao SC, Yuan T, Zhang YL et al. 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 2017;7:18095. https://doi.org/10.7150/thno.17133.

[106] Yu E, Zhang M, Xu G et al. Consensus cluster analysis of apoptosis-related genes in patients with osteoarthritis and their correlation with immune cell infiltration. Front Immunol 2023;14:1202758. https://doi.org/10.3389/fimmu.2023.1202758.

[107] Wang Y, Fan A, Lu L et al. Exosome modification to better alleviates endoplasmic reticulum stress induced chondrocyte apoptosis and osteoarthritis. Biochem Pharmacol 2022;206:115343. https://doi.org/10.1016/j.bcp.2022.115343.

[108] Xu C, Zhai Z, Ying H et al. Curcumin primed ADMSCs derived small extracellular vesicle exert enhanced protective effects on osteoarthritis by inhibiting oxidative stress and chondrocyte apoptosis. J Nanobiotechnol 2022;20:123. https://doi.org/10.1186/s12951-022-01339-3.

[109] Mariño G, Niso-Santano M, Baehrecke EH et al. Selfconsumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014;15:81-94. https://doi.org/10.1038/nrm3735.

[110] Wang Y, He SH, Liang X et al. ATF4-modified serum exosomes derived from osteoarthritic mice inhibit osteoarthritis by inducing autophagy. IUBMB Life 2021;73:146-58. https://doi.org/10.1002/iub.2414.

[111] Wu J, Kuang L, Chen C et al. 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 2019;206:87-100. https://doi.org/10.1016/j.biomaterials.2019.03.022.

[112] An S, Hu H, Li Y et al. Pyroptosis plays a role in osteoarthritis. Aging and disease 2020;11:1146-57. https://doi.org/10.14336/AD.2019.1127.

[113] Zhao LR, Xing RL, Wang PM et al. NLRP1 and NLRP3 inflammasomes mediate LPS/ATPinduced pyroptosis in knee osteoarthritis. Mol Med Rep 2018;17:5463-9. https://doi.org/10.3892/mmr.2018.8520.

[114] Zu Y, Mu Y, Li Q et al. Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis. J Orthop Surg Res 2019;14:307. https://doi.org/10.1186/s13018-019-1307-6.

[115] Xu H, Xu B. BMSC-derived exosomes ameliorate osteoarthritis by inhibiting pyroptosis of cartilage via delivering miR-326 targeting HDAC3 and STAT1//NF-κb p65 to chondrocytes. Medi-ators Inflamm 2021;2021:1. https://doi.org/10.1155/2021/9972805.

[116] Seibt TM, Proneth B, Conrad M. Role of GPX4 in ferroptosis and its pharmacological implication. Free Radical Biol Med 2019;133:144-52. https://doi.org/10.1016/j.freeradbiomed.2018.09.014.

[117] Yao X, Sun K, Yu S et al. Chondrocyte ferroptosis contribute to the progression of osteoarthritis. Journal of Orthopaedic Translation 2021;27:33-43. https://doi.org/10.1016/j.jot.2020.09.006.

[118] Zhang S, Xu J, Si H et al. The role played by ferroptosis in osteoarthritis: evidence based on iron dyshomeostasis and lipid peroxidation. Antioxidants 2022;11:1668. https://doi.org/10.3390/antiox11091668.

[119] Miao Y, Chen Y, Xue F et al. Contribution of ferroptosis and GPX4's dual functions to osteoarthritis progression. EBioMedicine 2022;76:103847. https://doi.org/10.1016/j.ebiom.2022.103847.

[120] Kong R, Ji L, Pang Y et al. Exosomes from osteoarthritic fibroblast-like synoviocytes promote cartilage ferroptosis and damage via delivering microRNA-19b-3p to target SLC7A 11 in osteoarthritis. Front Immunol 2023;14:1181156. https://doi.org/10.3389/fimmu.2023.1181156.

[121] Cheng S, Xu X, Wang R et al. Chondroprotective effects of bone marrow mesenchymal stem cell-derived exosomes in osteoarthritis. J Bioenerg Biomembr 2024;56:31-44. https://doi.org/10.1007/s10863-023-09991-6.

[122] Haseeb A, Haqqi TM. Immunopathogenesis of osteoarthritis. Clin Immunol 2013;146:185-96. https://doi.org/10.1016/j.clim.2012.12.011.

[123] Smith MD, Triantafillou S, Parker A et al. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 1997;24:365-71.

[124] Ishii H, Tanaka H, Katoh K et al. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis Cartilage 2002;10:277-81. https://doi.org/10.1053/joca.2001.0509.

[125] Zhao X, Zhao Y, Sun X et al. Immunomodulation of MSCs and MSC-derived extracellular vesicles in osteoarthritis. Front Bioeng Biotechnol 2020;8:575057. https://doi.org/10.3389/fbioe.2020.575057.

[126] Revell PA, Mayston V, Lalor P et al. The synovial membrane in osteoarthritis: a histological study including the characterisation of the cellular infiltrate present in inflammatory osteoarthritis using monoclonal antibodies. Ann Rheum Dis 1988;47:300-7. https://doi.org/10.1136/ard.47.4.300.

[127] Shen PC, Wu CL, Jou IM et al. T helper cells promote disease progression of osteoarthritis by inducing macrophage inflammatory protein-1γ. Osteoarthritis Cartilage 2011;19:728-36. https://doi.org/10.1016/j.joca.2011.02.014.

[128] Haringman JJ, Smeets TJ, Reinders-Blankert P et al. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann Rheum Dis 2006;65:294-300. https://doi.org/10.1136/ard.2005.037176.

[129] Nakamura H, Tanaka M, Masuko-Hongo K et al. Enhanced production of MMP-1, MMP-3, MMP-13, and RANTES by interaction of chondrocytes with autologous T cells. Rheumatol Int 2006;26:984-90. https://doi.org/10.1007/s00296-006-0116-5.

[130] Nedunchezhiyan U, Varughese I, Sun AR et al. Obesity, inflammation, and immune system in osteoarthritis. Front Immunol 2022;13:907750. https://doi.org/10.3389/fimmu.2022.907750.

[131] Ragni E, Perucca Orfei C, de Girolamo L. Secreted factors and extracellular vesicles account for the immunomodulatory and tissue regenerative properties of bone-marrow-derived mesenchymal stromal cells for osteoarthritis. Cells 2022;11:3501. https://doi.org/10.3390/cells11213501.

[132] Yin B, Ni J, Witherel CE et al. Harnessing tissue-derived extracellular vesicles for osteoarthritis theranostics. Theranostics 2022;12:207-31. https://doi.org/10.7150/thno.62708.

[133] Zhang S, Chuah SJ, Lai RC et al. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials 2018;156:1627. https://doi.org/10.1016/j.biomaterials.2017.11.028.

[134] Zheng L, Wang Y, Qiu P et al. Primary chondrocyte exosomes mediate osteoarthritis progression by regulating mitochondrion and immune reactivity. Nanomedicine (Lond.) 2019;14:3193-212. https://doi.org/10.2217/nnm-2018-0498.

[135] Li K, Yan G, Huang H et al. Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages. J Nanobiotechnol 2022;20:38. https://doi.org/10.1186/s12951-021-01236-1.

[136] Goldring SR. Alterations in periarticular bone and cross talk between subchondral bone and articular cartilage in osteoarthritis. Therapeutic Advances in Musculoskeletal 2012;4:24958. https://doi.org/10.1177/1759720X12437353.

[137] Portal-Núñez S, Lozano D, Esbrit P. Role of angiogenesis on bone formation. Histol Histopathol 2012;27:559-66. https://doi.org/10.14670/HH-27.559.

[138] Percival CJ, Richtsmeier JT. Angiogenesis and intramembranous osteogenesis. Dev Dyn 2013;242:909-22. https://doi.org/10.1002/dvdy.23992.

[139] Komori T, Yagi H, Nomura S et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997;89:755-64. https://doi.org/10.1016/S0092-8674(00)80258-5.

[140] Colnot C, de la Fuente L, Huang S et al. Indian hedgehog synchronizes skeletal angiogenesis and perichondrial maturation with cartilage development. Development 2005;132:1057-67. https://doi.org/10.1242/dev.01649.

[141] Wang R, Xu B. TGF β1-modified MSC-derived exosome attenuates osteoarthritis by inhibiting PDGF-BB secretion and Htype vessel activity in the subchondral bone. Acta Histochem 2022;124:151933. https://doi.org/10.1016/j.acthis.2022.151933.

[142] Zhao J, Sun Y, Sheng X et al. Hypoxia-treated adipose mesenchymal stem cell-derived exosomes attenuate lumbar facet joint osteoarthritis. Mol Med 2023;29:120. https://doi.org/10.1186/s10020-023-00709-3.

[143] Goldring MB. Update on the biology of the chondrocyte and new approaches to treating cartilage diseases. Best Practice & Research Clinical Rheumatology 2006;20:1003-25. https://doi.org/10.1016/j.berh.2006.06.003.

[144] Riazifar M, Pone EJ, Lötvall J et al. Stem cell extracellular vesicles: extended messages of regeneration. Annu Rev Pharmacol Toxicol 2017;57:125-54. https://doi.org/10.1146/annurev-pharmtox-061616-030146.

[145] Liu Y, Lin L, Zou R et al. MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis. Cell Cycle 2018;17:2411-22. https://doi.org/10.1080/15384101.2018.1526603.

[146] Liu Y, Zou R, Wang Z et al. Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochem J 2018;475:3629-38. https://doi.org/10.1042/BCJ20180675.

[147] Vonk LA, Liv N et al. Mesenchymal stromal/stem cell-derived extracellular vesicles promote Human cartilage regeneration In vitro. Theranostics 2018;8:906-20. https://doi.org/10.7150/thno.20746.

[148] Yin H, Li M, Tian G et al. The role of extracellular vesicles in osteoarthritis treatment via microenvironment regulation. Biomater Res 2022;26:52. https://doi.org/10.1186/s40824-022-00300-7.

[149] Nguyen TH, Dao HH, Duong CM et al. Cytokine-primed umbilical cord mesenchymal stem cells enhanced therapeutic effects of extracellular vesicles on osteoarthritic chondrocytes. Front Immunol 2022;13:1041592. https://doi.org/10.3389/fimmu.2022.1041592.

[150] Chen P, Zheng L, Wang Y et al. Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration. Theranostics 2019;9:2439-59. https://doi.org/10.7150/thno.31017.

[151] Ragni E, Perucca Orfei C,De Luca P et al. Secreted factors and EV-miRNAs orchestrate the healing capacity of adipose mesenchymal stem cells for the treatment of knee osteoarthritis. IntJ Mol Sci 2020;21:1582. https://doi.org/10.3390/ijms21051582.

[152] Shao LT, Luo L, Qiu JH et al. PTH (1-34) enhances the therapeutic effect of bone marrow mesenchymal stem cell-derived exosomes by inhibiting proinflammatory cytokines expression on OA chondrocyte repair in vitro. Arthritis Res Ther 2022;24:96. https://doi.org/10.1186/s13075-022-02778-x.

[153] Silver FH, Bradica G, Tria A. Do changes in the mechanical properties of articular cartilage promote catabolic destruction of cartilage and osteoarthritis? Matrix Biol 2004;23:467-76. https://doi.org/10.1016/j.matbio.2004.08.003.

[154] Fujii Y, Liu L, Yagasaki L et al. Cartilage homeostasis and osteoarthritis. Int J Mol Sci 2022;23:6316. https://doi.org/10.3390/ijms23116316.

[155] Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol 2010;6:625-35 https://doi.org/10.1038/nrrheum.2010.159.

[156] Eitner A, Hofmann GO, Schaible HG. Mechanisms of osteoarthritic pain. Studies in humans and experimental models. Front. Mol. Neurosci. 2017;10:349. https://doi.org/10.3389/fnmol.2017.00349.

[157] Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. The Lancet 2005;365:965-73. https://doi.org/10.1016/S0140-6736(05)71086-2.

[158] Duong V, Oo WM, Ding C et al. Evaluation and treatment of knee pain: A review. JAMA 2023;330:1568-80. https://doi.org/10.1001/jama.2023.19675.

[159] Nguyen TH, Duong CM, Nguyen XH et al. Mesenchymal stem cell-derived extracellular vesicles for osteoarthritis treatment: extracellular matrix protection, chondrocyte and osteocyte physiology, pain and inflammation management. Cells 2021;10:2887. https://doi.org/10.3390/cells10112887.

[160] D'Agnelli S, Gerra MC, Bignami E et al. Exosomes as a new pain biomarker opportunity. Mol Pain 2020;16:1744806920957800. https://doi.org/10.1177/1744806920957800.

[161] Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migrain. Paine 2017; 158:543-59. https://doi.org/10.1097/j.pain.0000000000000831.

[162] He L, He T, Xing J et al. Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis. Stem Cell Res Ther 2020;11:276. https://doi.org/10.1186/s13287-020-01781-w.

[163] Li J, Ding Z, Li Y et al. BMSCs-derived exosomes ameliorate pain via abrogation of aberrant nerve invasion in subchondral bone in lumbar facet joint osteoarthritis. Journal Orthopaedic Research 2020;38:670-9. https://doi.org/10.1002/jor.24497.

[164] Yang Q, Yao Y, Zhao D et al. LncRNA H19 secreted by umbilical cord blood mesenchymal stem cells through microRNA-29a-3p/FOS axis for central sensitization of pain in advanced osteoarthritis. Am J Transl Res 2021;13:1245-56.

[165] Lee YH, Park HK, Auh QS et al. Emerging potential of exosomes in regenerative medicine for temporomandibular joint osteoarthritis. Int J Mol Sci 2020;21:1541. https://doi.org/10.3390/ijms21041541.

[166] Zhang S, Teo KYW, Chuah SJ et al. MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials 2019;200:35-47. https://doi.org/10.1016/j.biomaterials.2019.02.006.

[167] Thomas BL, Eldridge SE, Nosrati B et al. WNT3A-loaded exosomes enable cartilage repair. J Extracellular Vesicle 2021;10:e12088. https://doi.org/10.1002/jev2.12088.

[168] Freyria AM, Mallein-Gerin F. Chondrocytes or adult stem cells for cartilage repair: the indisputable role of growth factors. Injury 2012;43:259-65. https://doi.org/10.1016/j.injury.2011.05.035.

[169] Deng ZH, Li YS, Gao X et al. Bone morphogenetic proteins for articular cartilage regeneration. Osteoarthritis Cartilage 2018;26:1153-61. https://doi.org/10.1016/j.joca.2018.03.007.

[170] Ude CC, Shamsul BS, Ng MH et al. Long-term evaluation of osteoarthritis sheep knee, treated with TGF-β3 and BMP-6 induced multipotent stem cells. Exp Gerontol 2018;104:43-51. https://doi.org/10.1016/j.exger.2018.01.020.

[171] Cheng J, Sun Y, Ma Y et al. Engineering of MSC-derived exosomes: A promising cell-free therapy for osteoarthritis. Membranes 2022;12:739. https://doi.org/10.3390/membranes12080739.

[172] Cosenza S, Ruiz M, Toupet K et al. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep 2017;7:16214. https://doi.org/10.1038/s41598-017-15376-8.

[173] Fu Y, Cui S, Zhou Y et al. Dental pulp stem cell-derived exosomes alleviate mice knee osteoarthritis by inhibiting TRPV4mediated osteoclast activation. Int J Mol Sci 2023;24:4926. https://doi.org/10.3390/ijms24054926.

[174] Mouamnia A, Desvages A. AB 0807 Toast-study: Treatment and osteoarthritis, what are people saying on Twitter? Ann Rheum Dis 2021;80:1427.3-1428. https://doi.org/10.1136/annrheumdis-2021-eular.3299.

[175] Kloek CJJ, van Dongen JM, de Bakker DH et al. Cost-effectiveness of a blended physiotherapy intervention compared to usual physiotherapy in patients with hip and/or knee osteoarthritis: a cluster randomized controlled trial. BMC Public Health 2018;18:1082. https://doi.org/10.1186/s12889-018-5975-7.

[176] Jones SE, Campbell PK, Kimp AJ et al. Evaluation of a novel e-learning program for physiotherapists to manage knee osteoarthritis via telehealth: qualitative study nested in the PEAK (Physiotherapy Exercise and Physical Activity for Knee Osteoarthritis) randomized controlled trial. J Med Internet Res 2021;23:e25872. https://doi.org/10.2196/25872.

[177] Perry TA, Wang X, Nevitt M et al. Association between current medication use and progression of radiographic knee osteoarthritis: data from the osteoarthritis initiative. Rheumatology (Oxford) 2021;60:4624-32. https://doi.org/10.1093/rheumatology/keab059.

[178] Madry H. Surgical therapy in osteoarthritis. Osteoarthritis Cartilage 2022;30:1019-34. https://doi.org/10.1016/j.joca.2022.01.012.

[179] Abram SGF, Judge A, Beard DJ et al. Long-term rates of knee arthroplasty in a cohort of 834393 patients with a history of arthroscopic partial meniscectomy. The Bone & Joint Journal 2019;101-B:1071-80. https://doi.org/10.1302/0301-620X.101B9.BJJ-2019-0335.R1.

[180] Bryan AJ, Krych AJ, Pareek A et al. Are short-term outcomes of hip arthroscopy in patients 55 years and older inferior to those in younger patients?. Am J Sports Med 2016;44:2526-30. https://doi.org/10.1177/0363546516652114.

[181] Hevesi M, Leland DP, Rosinsky PJ et al. Risk of conversion to arthroplasty after hip arthroscopy: validation of a published Risk score using an independent, prospectively collected database. Am J Sports Med 2021;49:1192-8. https://doi.org/10.1177/0363546521993829.

[182] Compton J, Slattery M, Coleman M et al. Iatrogenic articular cartilage injury in arthroscopic hip and knee videos and the potential for cartilage cell death when simulated in a bovine model. Arthroscopy: The Journal of Arthroscopic & Related Surgery 2020;36:2114-21. https://doi.org/10.1016/j.arthro.2020.02.017.

[183] Slomski A. Corticosteroid and lidocaine injection for hip osteoarthritis. JAMA 2022;327:1950. https://doi.org/10.1001/jama.2022.8170.

[184] Deyle GD, Allen CS, Allison SC et al. Physical therapy versus glucocorticoid injection for osteoarthritis of the knee. N Engl J Med 2020;382:1420-9. https://doi.org/10.1056/NEJMoa1905877.

[185] Zhang W, Ouyang H, Dass CR et al. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Res 2016;4:15040. https://doi.org/10.1038/boneres.2015.40.

[186] Cho Y, Jeong S, Kim H et al. Disease-modifying therapeutic strategies in osteoarthritis: current status and future directions. Exp Mol Med 2021;53:1689-96. https://doi.org/10.1038/s12276-021-00710-y.

[187] Deng J, Zong Z, Su Z et al. Recent advances in pharmacological intervention of osteoarthritis: A biological aspect. Front Pharmacol 2021;12:772678. https://doi.org/10.3389/fphar.2021.772678.

[188] Whitney KE, Liebowitz A, Bolia IK et al. Current perspectives on biological approaches for osteoarthritis. Ann NY Acad Sci 2017;1410:26-43. https://doi.org/10.1111/nyas.13554.

[189] Knights AJ, Redding SJ, Maerz T. Inflammation in osteoarthritis: the latest progress and ongoing challenges. Curr Opin Rheumatol 2023;35:128-34. https://doi.org/10.1097/BOR.0000000000000923.

[190] Xiang XN, Zhu SY, He HC et al. Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis. Stem Cell Res Ther 2022;13:14. https://doi.org/10.1186/s13287-021-02689-9.

[191] Burke J, Hunter M, Kolhe R et al. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. Clinical & Translational Med 2016;5:27. https://doi.org/10.1186/s40169-016-0112-7.

[192] Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. Cell Mol Immunol 2023;20:626-50. https://doi.org/10.1038/s41423-023-01020-1.

[193] Tevlin R, desJardins-Park H, Huber J et al. Musculoskeletal tissue engineering: adipose derived stromal cell implementation for the treatment of osteoarthritis. Biomaterials 2022;286:121544. https://doi.org/10.1016/j.biomaterials.2022.121544.

[194] Mak CCH, To K, Fekir K et al. Infrapatellar fat pad adiposederived stem cells co-cultured with articular chondrocytes from osteoarthritis patients exhibit increased chondrogenic gene expression. Cell Commun Signal 2022;20:17. https://doi.org/10.1186/s12964-021-00815-x.

[195] Liang H, Suo H, Wang Z et al. Progress in the treatment of osteoarthritis with umbilical cord stem cells. Hum Cell 2020;33:470-5. https://doi.org/10.1007/s13577-020-00377-z.

[196] Yamashita A, Yoshitomi H, Kihara S et al. Culture substrateassociated YAP inactivation underlies chondrogenic differentiation of human induced pluripotent stem cells. Stem Cells Transl Med 2021;10:115-27. https://doi.org/10.1002/sctm.20-0058.

[197] Castro-Viñuelas R, Sanjurjo-Rodríguez C, Piñeiro-Ramil M et al. Induced pluripotent stem cells for cartilage repair: current status and future perspectives. eCM 2018;36:96-109. https://doi.org/10.22203/eCM.v036a08.

[198] Abe K, Yamashita A, Morioka M et al. Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect. Nat Commun 2023;14:804. https://doi.org/10.1038/s41467-023-36408-0.

[199] Tatebe M, Nakamura R, Kagami H et al. Differentiation of transplanted mesenchymal stem cells in a large osteochondral defect in rabbit. Cytotherapy 2005;7:520-30. https://doi.org/10.1080/14653240500361350.

[200] Loo SJQ, Wong NK. Advantages and challenges of stem cell therapy for osteoarthritis (Review). Biomed Rep 2021;15:67. https://doi.org/10.3892/br.2021.1443.

[201] Turinetto V, Vitale E, Giachino C. Senescence in Human mesenchymal stem cells: functional changes and implications in stem cell-based therapy. Int J Mol Sci 2016;17:1164. https://doi.org/10.3390/ijms17071164.

[202] Irioda AC, Cassilha R, Zocche L et al. Human adiposederived mesenchymal stem cells cryopreservation and thawing decrease α4-integrin expression. Stem Cells International 2016;2016:2562718. https://doi.org/10.1155/2016/2562718.

[203] Shang Z, Wanyan P, Zhang B et al. A systematic review, umbrella review, and quality assessment on clinical translation of stem cell therapy for knee osteoarthritis: are we there yet?. Stem Cell Res Ther 2023;14:91. https://doi.org/10.1186/s13287-023-03332-5.

[204] Filardo G, Madry H, Jelic M et al. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopaedics. Knee Surg Sports Traumatol Arthrosc 2013;21:1717-29. https://doi.org/10.1007/s00167-012-2329-3.

[205] Tasso R, Augello A, Carida' M et al. Development of sarcomas in mice implanted with mesenchymal stem cells seeded onto bioscaffolds. Carcinogenesis 2009;30:150-7. https://doi.org/10.1093/carcin/bgn234.

[206] Kim SY, Lee DG, Kim MS et al. The influence of infection early after allogeneic stem cell transplantation on the risk of leukemic relapse and graft-versus-host disease. American J Hematol 2008;83:784-8. https://doi.org/10.1002/ajh.21227.

[207] Shapiro RS. Future issues in transplantation ethics: ethical and legal controversies in xenotransplantation, stem cell, and cloning research. Transplant Rev (Orlando) 2008;22:210-4. https://doi.org/10.1016/j.trre.2008.04.004.

[208] Shah SS, Mithoefer K. Current applications of growth factors for knee cartilage repair and osteoarthritis treatment. Curr Rev Musculoskelet Med 2020;13:641-50. https://doi.org/10.1007/s121 78-020-09664-6.

[209] Strauss EJ, Barker JU, Kercher JS et al. Augmentation strategies following the microfracture technique for repair of focal chon-dral defects. Cartil 2010;1:145-52. https://doi.org/10.1177/1947603510366718.

[210] Everts P, Onishi K, Jayaram P et al. Platelet-rich plasma: new performance understandings and therapeutic considerations in 2020. Int J Mol Sci 2020;21:7794. https://doi.org/10.3390/ijms21207794.

[211] Cao Y, Luo J, Han S et al. A model-based quantitative analysis of efficacy and associated factors of platelet rich plasma treatment for osteoarthritis. Int J Surg 2023;109:1742-52. https://doi.org/10.1097/JS9.0000000000000337.

[212] Le ADK, Enweze L, DeBaun MR et al. Platelet-rich plasma. Clin Sports Med 2019;38:17-44. https://doi.org/10.1016/j.csm.2018.08.001.

[213] Zhao D, Pan JK, Yang WY et al. Intra-articular injections of platelet-rich plasma, adipose mesenchymal stem cells, and bone marrow mesenchymal stem cells associated with better outcomes than hyaluronic acid and saline in knee osteoarthritis: A systematic review and network meta-analysis. Arthroscopy: The Journal of Arthroscopic & Related Surgery 2021;37:2298-314. https://doi.org/10.1016/j.arthro.2021.02.045.

[214] Louis ML, Magalon J, Jouve E et al. Growth factors levels determine efficacy of platelets rich plasma injection in knee osteoarthritis: A randomized double blind noninferiority trial compared with viscosupplementation. Arthroscopy: The Journal of Arthroscopic & Related Surgery 2018;34:1530-40. https://doi.org/10.1016/j.arthro.2017.11.035.

[215] Park YB, Kim JH, Ha CW et al. Clinical efficacy of platelet-rich plasma injection and its association with growth factors in the treatment of mild to moderate knee osteoarthritis: A randomized double-blind controlled Clinical trial As compared with hyaluronic acid. Am J Sports Med 2021;49:487-96. https://doi.org/10.1177/0363546520986867.

[216] Ratneswaran A, Kapoor M. Osteoarthritis year in review: genetics, genomics, epigenetics. Osteoarthritis Cartilage 2021;29:15160. https://doi.org/10.1016/j.joca.2020.11.003.

[217] Young DA, Barter MJ, Soul J. Osteoarthritis year in review: genetics, genomics, epigenetics. Osteoarthritis Cartilage 2022;30:216-25. https://doi.org/10.1016/j.joca.2021.11.004.

[218] Rice SJ, Beier F, Young DA et al. Interplay between genetics and epigenetics in osteoarthritis. Nat Rev Rheumatol 2020;16:268-81. https://doi.org/10.1038/s41584-020-0407-3.

[219] Loughlin J. Translating osteoarthritis genetics research: challenging times ahead. Trends Mol Med 2022;28:176-82. https://doi.org/10.1016/j.molmed.2021.12.007.

[220] Boer CG, Hatzikotoulas K, Southam L et al. Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations. Cell 2021;184:4784-818. https://doi.org/10.1016/j.cell.2021.07.038.

[221] Attur M, Zhou H, Samuels J et al. Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease. Ann Rheum Dis 2020;79:400-7. https://doi.org/10.1136/annrheumdis-2019-216055.

[222] Aubourg G, Rice SJ, Bruce-Wootton P et al. Genetics of osteoarthritis. Osteoarthritis Cartilage 2022;30:636-49. https://doi.org/10.1016/j.joca.2021.03.002.

[223] Hartley A, Gregson CL, Paternoster L et al. Osteoarthritis: insights offered by the study of bone mass genetics. Curr Osteoporos Rep 2021;19:115-22. https://doi.org/10.1007/s11914-021-00655-1.