Molekulyarnaya Meditsina (Molecular medicine)Molekulyarnaya Meditsina (Molecular medicine)Молекулярная медицина1728-29182499-9490Russkiy Vrach Publishing House30367210.29296/24999490-2023-01-02ReviewsОбзорыReview ArticleThe use of mesenchymal stem cells in the treatment of osteoarthritisПрименение мезенхимальных стволовых клеток в лечении остеоартритаhttps://orcid.org/0000-0002-2423-523XGrebenAnastasiya I.ГребеньАнастасия Игоревна
Russian Federation

Resident, Pirogov Russian National Research Medical University. Junior researcher, National Medical Research Center for Rehabilitation and Balneology

Ординатор кафедры травматологии, ортопедии и военно-полевой хирургии ПФ, Российский национальный исследовательский медицинский университет им. Н.И. Пирогова. Младший научный сотрудник, Национальный медицинский исследовательский центр реабилитации и курортологии Минздрава России

aik-nastya@mail.ruhttps://orcid.org/0000-0002-6271-3108ShestakovDmitry Y.ШестаковДмитрий Юрьевич
Russian Federation

Ph.D. Head of the Department of Orthopedics and Complex Trauma, State Budgetary Institution of Healthcare, Moscow Clinical Research Center named after A.S. Loginov

к.м.н. заведующий отделением ортопедии и сложной травмы ГБУЗ «Московский клинический научный центр им. А.С. Логинова»

dimitrauma@bk.ruhttps://orcid.org/0000-0001-8832-8470EreminPeter S.ЕреминПетр Серафимович
Russian Federation

Researcher, National Medical Research Center for Rehabilitation and Balneology

научный сотрудник, Национальный медицинский исследовательский центр реабилитации и курортологии Минздрава России

ereminps@gmail.comhttps://orcid.org/0000-0002-9728-7938KostrominaElena Y.КостроминаЕлена Юрьевна
Russian Federation

Cand. Sci. (Bio.), Senior Researcher, National Medical Research Center for Rehabilitation and Balneology

кандидат биологических наук, старший научный сотрудник, Национальный медицинский исследовательский центр реабилитации и курортологии Минздрава России

bioimed07@hotmail.comhttps://orcid.org/0000-0002-4803-4803MarkovPavel A.МарковПавел Александрович
Russian Federation

Cand. Sci. (Bio.), Senior Researcher, National Medical Research Center for Rehabilitation and Balneology

кандидат биологических наук, старший научный сотрудник, Национальный медицинский исследовательский центр реабилитации и курортологии Минздрава России

p.a.markov@mail.ruhttps://orcid.org/0000-0002-6001-0804GrebenTatiana N.ГребеньТатьяна Николаевна
Russian Federation

Deputy Chief Medical Officer, National Medical Research Center for Rehabilitation and Balneology

заместитель главного врача по медицинской части, Национальный медицинский исследовательский центр реабилитации и курортологии Минздрава России

greben72@inbox.ruhttps://orcid.org/0000-0001-6743-2615GilmutdinovaIlmira R.ГильмутдиноваИльмира Ринатовна
Russian Federation

Cand. Sci. (Med.), Head of the Department of Biomedical Technologies, National Medical Research Center for Rehabilitation and Balneology

кандидат медицинских наук, заведующая отделом биомедицинских технологий, Национальный медицинский исследовательский центр реабилитации и курортологии Минздрава России

gilm.ilmira@mail.ruPirogov Russian National Research Medical UniversityРоссийский национальный исследовательский медицинский университет им. Н.И. ПироговаNational Medical Research Center for Rehabilitation and BalneologyФГБУ «Национальный медицинский исследовательский центр реабилитации и курортологии» Министерства здравоохранения Российской ФедерацииGBUZ Moscow Clinical Scientific Center named after A.S. Loginov DZMГБУЗ Московский клинический научный Центр им. А.С. Логинова ДЗМ010320232118150103202301032023Copyright ©; 2023, Russkiy Vrach Publishing HouseCopyright ©; 2023, ИД "Русский врач"2023Russkiy Vrach Publishing HouseИД "Русский врач"https://journals.eco-vector.com/1728-2918/article/view/303672

The purpose of the study was to analyze literature data on the use of mesenchymal stem cells as a conservative treatment of osteoarthritis.

Material and methods. Literature search was carried out using keywords: traumatology, orthopedics, mesenchymal stem cells, osteoarthritis, cell therapy. Out of 300 selected articles, 60 were used to write a review.

Results. Osteoarthritis treatment with mesenchymal stem cells has been shown to be effective and safe in cartilage repair in both animal and human studies. The review presents new literature data on therapeutic action mechanisms and elements of mesenchymal stem cells.

Conclusion. The analysis shows that a positive experience of using mesenchymal stem cells (MSCs’) for osteoarthritis treatment. However, before mesenchymal stem cells take their place in practical tools arsenal a lot of work must be done, specifically: phase III of clinical trials, clear criteria development defining cell culture as MSCs, development of production standards and further study of MSCs’ mechanism of action in osteoarthritis.

Цель исследования – анализ литературных данных об использовании мезенхимальных столовых клеток в качестве консервативного лечения остеоартрита.

Материал и методы. Анализ зарубежной литературы по ключевым словам: травматология, ортопедия, мезенхимальные столовые клетки, остеоартрит, клеточная терапия. В ходе анализа было отобрано более 300 статей, 60 из них использовались для написания обзора.

Результаты. Лечение остеоартрита мезенхимальными стволовыми клетками продемонстрировало свою эффективность и безопасность в восстановлении хрящевой ткани, как в исследованиях на животных, так и в испытаниях на людях. В обзоре представлены новые данные литературы о механизмах и элементах терапевтического действия мезенхимальных столовых клеток.

Заключение. Проведенный анализ свидетельствует о том, что к настоящему времени накоплен определенный положительный опыт применения мезенхимальных стволовых клеток в лечении остеоартрита. Однако, прежде чем МСК займут свое место в арсенале практических средств, должна быть проведена большая работа, а именно: клинические исследования 3 фазы, выработка четких критериев, определяющих культуру клеток, как МСК; разработка производственных стандартов и дальнейшее исследование механизмов действия МСК при остеоартрите.

traumatologyorthopedicsmesenchymal stem cellsosteoarthritiscell therapyтравматологияортопедиямезенхимальные столовые клеткиостеоартритклеточная терапияZhao X., Zhao Y., Sun X., Xing Y., Wang X., Yang Q. Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis. Front Bioeng Biotechnol. 2020; 29: 8. https://doi.org/10.3389/fbioe.2020.575057.Hunter D.J., Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019; 393: 1745–59. https://doi.org/0.1016/S0140-6736(19)30417-9.De Bari C., Roelofs A.J. Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. Curr Opin Pharmacol. 2018; 40: 74–80. https://doi.org/10.1016/j.coph.2018.03.009.Song Y., Zhang J., Xu H., Lin Z., Chang H., Liu W., Kong L. Mesenchymal stem cells in knee osteoarthritis treatment: A systematic review and meta-analysis. J. Orthop Translat. 2020; 27; 24: 121–30. https://doi.org/10.1016/j.jot.2020.03.015.Matas J., Orrego M., Amenabar D., Infante C., Tapia-Limonchi R., Cadiz M.I., Alcayaga-Miranda F., González P.L., Muse E., Khoury M., Figueroa F.E., Espinoza F. 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. 2019; 8 (3): 215–24. https://doi.org/10.1002/sctm.18-0053.Qiu B., Xu X., Yi P., Hao Y. Curcumin reinforces MSC-derived exosomes in attenuating osteoarthritis via modulating the miR-124/NF-kB and miR-143/ROCK1/TLR9 signalling pathways. J. Cell. Mol. Med. 2020; 24 (18): 10855–65. https://doi.org/10.1111/jcmm.15714.Mianehsaz E., Mirzaei H.R., Mahjoubin-Tehran M. et al. Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem Cell Res Ther. 2019; 10 (1): 340. https://doi.org/10.1186/s13287-019-1445-0Liu Y., Lin L., Zou R., Wen C., Wang Z., Lin F. MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis. Cell Cycle. 2018; 17 (21–22): 2411–22. https://doi.org/10.1080/15384101.2018.1526603.Guo W., Zheng X., Zhang W., Chen M., Wang Z., Hao C. et al. Mesenchymal Stem Cells in Oriented PLGA/ACECM Composite Scaffolds Enhance Structure-Specific Regeneration of Hyaline Cartilage in a Rabbit Model. Stem Cells International 2018; 18: 1–12. https://doi.org/10.1155/2018/6542198.Kamei N., Ochi M., Adachi N., Ishikawa M., Yanada S., Levin L.S. et al. The safety and efficacy of magnetic targeting using autologous mesenchymal stem cells for cartilage repair. Knee Surgery, Sports Traumatology. 2018; 26 (12): 3626–35. https://doi.org/10.1007/s00167-018-4898-2.Iijima H., Isho T., Kuroki H., Takahashi M., Aoyama T. Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: a meta-analysis toward the establishment of effective regenerative rehabilitation. npj Regenerative Medicine. 2018; 17: 1–9. https://doi.org/10.1038/s41536-018-0041-8Zhang R., Ma J., Han J., Zhang W., Ma J. Mesenchymal stem cell related therapies for cartilage lesions and osteoarthritis. Am. J. Transl Res. 2019; 11 (10): 6275–89.Lee Y.H., Park H.K., Auh Q.S., Nah H., Lee J.S., Moon H.J., Heo D.N., Kim I.S., Kwon I.K. Emerging Potential of Exosomes in Regenerative Medicine for Temporomandibular Joint Osteoarthritis. Int. J. Mol. Sci. 2020; 21 (4): 1541. https://doi.org/10.3390/ijms21041541.Xia T., Yu F., Zhang K., Wu Z., Shi D., Teng H., Shen J., Yang X., Jiang Q. The effectiveness of allogeneic mesenchymal stem cells therapy for knee osteoarthritis in pigs. Ann. Transl. Med. 2018; 6: 404. https://doi.org/10.21037/atm.2018.09.55.Kim H., Yang G., Park J., Choi J., Kang E., Lee B.K. Therapeutic effect of mesenchymal stem cells derived from human umbilical cord in rabbit temporomandibular joint model of osteoarthritis. Sci. Rep. 2019; 9: 13854. https://doi.org/10.1038/s41598-019-50435-2Barry F. MSC Therapy for Osteoarthritis: An Unfinished Story. Jю Orthop Res. 2019; 37 (6): 1229–35. https://doi.org/10.1002/jor.24343.Вагабов А.В., Темнов А.А., Толкачева В.В., Склифас А.Н., Кукушкин Н.И. Мезенхимальные стволовые клетки: опыт применения в экспериментальной и клинической медицине, механизмы действия. Клиническая фармакология и терапия. 2014; 23 (2): 72–7. [Vagabov A.V., Temnov A.A., Tolkacheva V.V., Slifas A.N., Kukushkin N.I. Mesenchymal stromal cells: experience of experimental and clinical use and mechanisms of action. Klinicheskaya pharmacologia i therapia. 2014; 23 (2): 72–7 (in Russian)].Pers Y.M., Rackwitz L., Ferreira R., Pullig O., Delfour C., Barry F., Sensebe L., Casteilla L., Fleury S., Bourin P., Noël D., Canovas F., Cyteval C., Lisignoli G., Schrauth J., Haddad D., Domergue S., Noeth U., Jorgensen C. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: A phase I dose-escalation trial. Stem Cells Translational Medicine. 2016; 5: 847–56. https://doi.org/10.5966/sctm.2015-0245.Xu M., Shaw G., Murphy M., Barry F. Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells Are Functionally and Genetically Different From Bone Marrow-Derived Mesenchymal Stromal Cells. Stem Cells. 2019; 37 (6): 754–65. https://doi.org/10.1002/stem.2993.Mancuso P., Raman S., Glynn A., Barry F., Murphy J.M. Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role of the Cell Secretome. Frontiers in Bioengineering and Biotechnology. 2019; 7: 1–9. https://doi.org/10.3389/fbioe.2019.00009.Im G.I. Tissue Engineering in Osteoarthritis: Current Status and Prospect of Mesenchymal Stem Cell Therapy. BioDrugs. 2018; 32 (3): 183–92. https://doi.org/10.1007/s40259-018-0276-3.Aspden R.M., Saunders F.R. Osteoarthritis as an organ disease: from the cradle to the grave. Eur Cells Mater. 2019; 37: 74–87. https://doi.org/10.22203/eCM.v037a06.Chow Y.Y., Chin K.Y. The Role of Inflammation in the Pathogenesis of Osteoarthritis. Mediators Inflamm. 2020: 8293921. https://doi.org/10.1155/2020/8293921.Fernandes T.L., Gomoll A.H., Lattermann C., Hernandez A.J., Bueno D.F., Amano M.T. Macrophage: a potential target on cartilage regeneration. Front. Immunol. 2020; 11: 111. https://doi.org/10.3389/fimmu.2020.00111.Wu C.L., Harasymowicz N.S., Klimak M.A., Collins K.H., Guilak F. The role of macrophages in osteoarthritis and cartilage repair. Osteoarthr. Cartilage. 2020; 28: 544–54. https://doi.org/10.1016/j.joca.2019.12.007.Oishi Y., Manabe I. Macrophages in inflammation, repair and regeneration. Int. Immunol. 2018; 30: 511–28. https://doi.org/10.1093/intimm/dxy054.Fernandes T.L., Gomoll A.H., Lattermann C., Hernandez A.J., Bueno D.F., Amano M.T. Macrophage: a potential target on cartilage regeneration. Front. Immunol. 2020; 11: 111. с10.3389/fimmu.2020.00111.Chen Y., Jiang W., Yong H., He M., Yang Y., Deng Z., et al. Macrophages in osteoarthritis: pathophysiology and therapeutics. Am. J. Transl. Res. 2020; 12: 261–8.Labinsky H., Panipinto P. M., Ly K. A., Khuat D. K., Madarampalli B., Mahajan V., et al. Multiparameter analysis identifies heterogeneity in knee osteoarthritis synovial responses. Arthritis Rheumatol. 2020; 72: 598–608. https://doi.org/10.1002/art.41161.Li Y.S., Luo W., Zhu S.A., Lei G. H. T cells in osteoarthritis: alterations and beyond. Front. Immunol. 2017; 8: 356. https://doi.org/10.3389/fimmu.2017.00356.Min H.K., Choi J., Lee S.Y., Seo H.B., Jung K., Na H.S. et al. Protein inhibitor of activated STAT3 reduces peripheral arthritis and gut inflammation and regulates the Th17/Treg cell imbalance via STAT3 signaling in a mouse model of spondyloarthritis. J. Transl. Med. 2019; 17: 18–28. https://doi.org/10.1186/s12967-019-1774-x.Peter J., Sabu V., Aswathy I. S., Krishnan S., Lal Preethi S.S., Simon M. et al. Dietary amaranths modulate the immune response via balancing Th1/Th2 and Th17/Treg response in collagen-induced arthritis. Mol. Cell. Biochem. 2020; 472: 57–66. https://doi.org/10.1007/s11010-020-03783-x.Zhu W., Zhang X., Jiang Y., Liu X., Huang L., Wei Q. et al. Alterations in peripheral T cell and B cell subsets in patients with osteoarthritis. Clin. Rheumatol. 2020; 39: 523–32. https://doi.org/10.1007/s10067-019-04768-y.Modinger Y., Rapp A.E., Vikman A., Ren Z.Z., Fischer V., Bergdolt S. et al. Reduced terminal complement complex formation in mice manifests in low bone mass and impaired fracture healing. Am. J. Pathol. 2019; 189: 147–61. https://doi.org/10.1016/j.ajpath.2018.09.011.Fernandez-Pernas P., Barrachina L., Marquina M., Rodellar C., Arufe M.C., Costa C. Mesenchymal stromal cells for articular cartilage repair: preclinical studies. Eur. Cell. Mater. 2020; 40: 88–114. https://doi.org/10.22203/eCM.v040a06.De Castro L.L., Lopes-Pacheco M., Weiss D.J., Cruz F.F., Rocco P.R.M. Current understanding of the immunosuppressive properties of mesenchymal stromal cells. J. Mol. Med. 2019; 97: 605–18. https://doi.org/10.1007/s00109-019-01776-y.Zhao L., Chen S., Yang P., Cao H., Li L. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease. Stem Cell Res. Ther. 2019; 10: 182. https://doi.org/10.1186/s13287-019-1287-9.Ayala-Cuellar A.P., Kang J.H., Jeung E.B., Choi K.C. Roles of mesenchymal stem cells in tissue regeneration and immunomodulation. Biomol. Ther. 2019; 27: 25–33. https://doi.org/10.4062/biomolther.2017.260.Lin L.Y., Du L.M. The role of secreted factors in stem cells-mediated immune regulation. Cell. Immunol. 2018; 326: 24–32. https://doi.org/10.1016/j.cellimm.2017.07.010.Park H.J., Kim J., Saima F.T., Rhee K.J., Hwang S., Kim M.Y. et al. Adipose-derived stem cells ameliorate colitis by suppression of inflammasome formation and regulation of M1-macrophage population through prostaglandin E2. Biochem. Biophys. Res. Commun. 2018; 498: 988–95. https://doi.org/10.1016/j.bbrc.2018.03.096.Shi X., Chen Q., Wang F. Mesenchymal stem cells for the treatment of ulcerative colitis: a systematic review and meta-analysis of experimental and clinical studies. Stem Cell Res. Ther. 2019; 10: 266. https://doi.org/10.1186/s13287-019-1336-4.Kyurkchiev D., Bochev I., Ivanova-Todorova E., Mourdjeva M., Oreshkova T., Belemezova K. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J. Stem Cells. 2014; 6: 552–70. https://doi.org/10.4252/wjsc.v6.i5.552.Behm C., Blufstein A., Gahn J., Nemec M., Moritz A., Rausch-Fan X. Cytokines differently define the immunomodulation of mesenchymal stem cells from the periodontal ligament. Cells. 2020; 9: 1222. https://doi.org/10.3390/cells9051222.Baharlou R., Rashidi N., Ahmadi-Vasmehjani A., Khoubyari M., Sheikh M., Erfanian S. Immunomodulatory effects of human adipose tissue-derived mesenchymal stem cells on T cell subsets in patients with rheumatoid arthritis. Iran. J. Allergy Asthma Immunol. 2019; 18: 114–9. https://doi.org/10.18502/ijaai.v18i1.637.Jimenez-Puerta G.J., Marchal J.A., Lopez-Ruiz E., Galvez-Martin P. Role of mesenchymal stromal cells as therapeutic agents: potential mechanisms of action and implications in their clinical use. J. Clin. Med. 2020; 9: 445. https://doi.org/10.3390/jcm9020445.Kim J.Y., Park M., Kim Y.H., Ryu K.H., Lee K.H., Cho K.A. Tonsil-derived mesenchymal stem cells (T-MSCs) prevent Th17-mediated autoimmune response via regulation of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway. J. Tissue Eng. Regen. Med. 2018; 12: 1022–33. https://doi.org/10.1002/term.2423.Carreras-Planella L., Monguió-Tortajada M., Borràs F., Franquesa M. Corrigendum: immunomodulatory effect of MSC on B cells is independent of secreted extracellular vesicles. Front. Immunol. 2019; 10: 2413. https://doi.org/10.3389/fimmu.2019.02413.Chen X., Cai C., Xu D., Liu Q., Zheng S., Liu L. Human mesenchymal stem cell-treated regulatory CD23(+)CD43(+) B cells alleviate intestinal inflammation. Theranostics. 2019; 9: 4633–47. https://doi.org/10.7150/thno.32260.Li B., Xu H., Han H., Song S., Zhang X., Ouyang L. Exosome-mediated transfer of lncRUNX2-AS1 from multiple myeloma cells to MSCs contributes to osteogenesis. Oncogene. 2018; 37 (41): 5508–19. https://doi.org/10.1038/s41388-018-0359-0.Zhang S., Chuah S.J., Lai R.C., Hui J.H.P., Lim S.K., Toh W.S. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018; 156: 16–27. https://doi.org/10.1016/j.biomaterials.2017.11.028.Liu Y., Zou R., Wang Z., Wen C., Zhang F., Lin F. Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochemical J. 2018; 475 (22): 3629–38. https://doi.org/10.1042/bcj20180675.Sun H., Hu S., Zhang Z., Lun J., Liao W., Zhang Z. Expression of exosomal microRNAs during chondrogenic differentiation of human bone mesenchymal stem cells. J. of Cellular Biochemistry. 2018; 120 (1): 171–81. https://doi.org/10.1002/jcb.27289.Ni Z., Shang X., Tang G., Niu L. Expression of miR-206 in Human Knee Articular Chondrocytes and Effects of miR-206 on Proliferation and Apoptosis of Articular Chondrocytes. The Am. J. of the Medical Sciences. 2018; 355 (3): 240–6. https://doi.org/10.1016/j.amjms.2017.11.003.Zhao T., Sun F., Liu J., Ding T., She J., Mao F., Xu W., Qian H., Yan Y. Emerging Role of Mesenchymal Stem Cell-derived Exosomes in Regenerative Medicine. Curr. Stem Cell Res. Ther. 2019; 14: 482–94. https://doi.org/10.2174/1574888X14666190228103230.Fuggle N.R., Cooper C., Oreffo R.O.C., Price A.J., Kaux J.F., Maheu E., Cutolo M., Honvo G., Conaghan P.G., Berenbaum F., Branco J., Brandi M.L., Cortet B., Veronese N., Kurth A.A., Matijevic R., Roth R., Pelletier J.P., Martel-Pelletier J., Vlaskovska M., Thomas T., Lems W.F., Al-Daghri N., Bruyère O., Rizzoli R., Kanis J.A., Reginster J.Y. Alternative and complementary therapies in osteoarthritis and cartilage repair. Aging Clin Exp Res. 2020; 32 (4): 547–60. https://doi.org/10.1007/s40520-020-01515-1.Arshi A., Petrigliano F.A., Williams R.J., Jones K.J. Stem Cell Treatment for Knee Articular Cartilage Defects and Osteoarthritis. Curr Rev Musculoskelet Med. 2020; 13(1): 20-27, https://doi.org/10.1007/s12178-020-09598-z.Hwang J.J., Rim Y.A., Nam Y., Ju J.H. Recent Developments in Clinical Applications of Mesenchymal Stem Cells in the Treatment of Rheumatoid Arthritis and Osteoarthritis. Front Immunol. 2021; 12: 631291. https://doi.org/10.3389/fimmu.2021.631291.Li N., Gao J., Mi L., Zhang G., Zhang L., Zhang N. Synovial membrane mesenchymal stem cells: past life, current situation, and application in bone and joint diseases. Stem Cell Res Ther. 2020; 11: 381. https://doi.org/10.1186/s13287-020-01885-3.URL: http://clinicaltrials.gov (Дата обращения 15.08.2022)URL: http://www.jcrpharm.co.jp/wp2/wp-content/uploads/2017/10/JCR-AR2017_English_FINAL1.pdf (Дата обращения 10.08.2022)