Exosomes May Be the Potential New Direction of Research in Osteoarthritis Management

Cheng Ju, Renfeng Liu, Yu Zhang, Feifei Zhang, Jun Sun, Xiao-Bin Lv, Zhiping Zhang, Cheng Ju, Renfeng Liu, Yu Zhang, Feifei Zhang, Jun Sun, Xiao-Bin Lv, Zhiping Zhang

Abstract

Osteoarthritis (OA) is a joint degenerative disease, which is prominent in the middle-aged and elderly population, often leading to repeated pain in the joints of patients and seriously affecting the life quality of patients. At present, the treatment of OA mainly depends on the surgery and drug treatment. Nevertheless, these treatments still face many problems, such as surgical safety, complications, and drug side effects. Exosomes can be secreted and released by multiple cell types and have lipid bilayer membranes and contain abundant biological molecules, including proteins, lipids, and nucleic acids. Moreover, exosomes play a critical role in local and distal intercellular and intracellular communication. In recent years, several studies have found that exosomes can regulate the progression of OA and have a potential efficacy for OA treatment. Thus, in this article, we summarize and review the relevant research of exosomes in OA and emphasize the importance of exosomes in the development of OA.

Conflict of interest statement

The authors declare no conflicts of interest.

Copyright © 2019 Cheng Ju et al.

Figures

Figure 1
Figure 1
Exosomal formation, release, and intercellular transmission. The formation of exosomes includes three stages: form endosomes, form ILVs and MVBs, and further are secreted to extracellular space. When exosomes are released, exosomes act as intercellular signaling molecules that interact with receptor cells, including binding to cell membrane surface proteins, direct fusion, and endocytosis.
Figure 2
Figure 2
The function of exosomes in OA. We describe the important functions of exosomes in OA through intra-articular injection and cell transfection, including promoting cartilage production, promoting cartilage repair, regulating inflammation, maintaining the cartilage matrix, and promoting chondrocyte proliferation and metastasis. These indicate the potential clinical value of exosomes for OA treatment.

References

    1. Loeser R. F., Goldring S. R., Scanzello C. R., Goldring M. B. Osteoarthritis: a disease of the joint as an organ. Arthritis & Rheumatism. 2012;64(6):1697–1707. doi: 10.1002/art.34453.
    1. Palazzo C., Ravaud J. F., Papelard A., Ravaud P., Poiraudeau S. The burden of musculoskeletal conditions. PLoS One. 2014;9(3) doi: 10.1371/journal.pone.0090633.e90633
    1. Lotz M. K., Kraus V. B. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Research & Therapy. 2010;12(3):p. 211. doi: 10.1186/ar3046.
    1. Glyn-Jones S., Palmer A. J. R., Agricola R., et al. Osteoarthritis. The Lancet. 2015;386(9991):376–387. doi: 10.1016/s0140-6736(14)60802-3.
    1. Dieppe P., Lim K., Lohmander S. Who should have knee joint replacement surgery for osteoarthritis? International Journal of Rheumatic Diseases. 2011;14(2):175–180. doi: 10.1111/j.1756-185x.2011.01611.x.
    1. Kiadaliri A. A., Lohmander L. S., Moradi-Lakeh M., Petersson I. F., Englund M. High and rising burden of hip and knee osteoarthritis in the Nordic region, 1990–2015. Acta Orthopaedica. 2018;89(2):177–183. doi: 10.1080/17453674.2017.1404791.
    1. Théry C., Zitvogel L., Amigorena S. Exosomes: composition, biogenesis and function. Nature Reviews Immunology. 2002;2(8):569–579. doi: 10.1038/nri855.
    1. 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 Research & Therapy. 2017;8(1):p. 189. doi: 10.1186/s13287-017-0632-0.
    1. Mao G., Hu S., Zhang Z., et al. Exosomal miR-95-5p regulates chondrogenesis and cartilage degradation via histone deacetylase 2/8. Journal of Cellular and Molecular Medicine. 2018;22(11):5354–5366. doi: 10.1111/jcmm.13808.
    1. Kato T., Miyaki S., Ishitobi H., et al. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Research & Therapy. 2014;16(4):p. R163. doi: 10.1186/ar4679.
    1. György B., Szabó T. G., Pásztói M., et al. Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles. Cellular and Molecular Life Sciences. 2011;68(16):2667–2688. doi: 10.1007/s00018-011-0689-3.
    1. Simons M., Raposo G. Exosomes—vesicular carriers for intercellular communication. Current Opinion in Cell Biology. 2009;21(4):575–581. doi: 10.1016/j.ceb.2009.03.007.
    1. Foers A. D., Chatfield S., Dagley L. F., et al. Enrichment of extracellular vesicles from human synovial fluid using size exclusion chromatography. Journal of Extracellular Vesicles. 2018;7(1) doi: 10.1080/20013078.2018.1490145.1490145
    1. Xu R., Greening D. W., Zhu H.-J., Takahashi N., Simpson R. J. Extracellular vesicle isolation and characterization: toward clinical application. Journal of Clinical Investigation. 2016;126(4):1152–1162. doi: 10.1172/jci81129.
    1. Gurunathan S., Kang M.-H., Jeyaraj M., Qasim M., Kim J.-H. Review of the isolation, characterization, biological function, and multifarious therapeutic approaches of exosomes. Cells. 2019;8(4) doi: 10.3390/cells8040307.
    1. Ha D., Yang N., Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: current perspectives and future challenges. Acta Pharmaceutica Sinica B. 2016;6(4):287–296. doi: 10.1016/j.apsb.2016.02.001.
    1. Qin J., Xu Q. Functions and application of exosomes. Acta Poloniae Pharmaceutica. 2014;71(4):537–543.
    1. Tai Y.-L., Chen K.-C., Hsieh J.-T., Shen T.-L. Exosomes in cancer development and clinical applications. Cancer Science. 2018;109(8):2364–2374. doi: 10.1111/cas.13697.
    1. Raposo G., Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. The Journal of Cell Biology. 2013;200(4):373–383. doi: 10.1083/jcb.201211138.
    1. Raposo G., Nijman H. W., Stoorvogel W., et al. B lymphocytes secrete antigen-presenting vesicles. Journal of Experimental Medicine. 1996;183(3):1161–1172. doi: 10.1084/jem.183.3.1161.
    1. Zhao H., Achreja A., Iessi E., et al. The key role of extracellular vesicles in the metastatic process. Biochimica et Biophysica Acta (BBA)—Reviews on Cancer. 2018;1869(1):64–77. doi: 10.1016/j.bbcan.2017.11.005.
    1. Lin J., Li J., Huang B., et al. Exosomes: novel biomarkers for clinical diagnosis. The Scientific World Journal. 2015;2015:8. doi: 10.1155/2015/657086.657086
    1. D’Adamo S., Cetrullo S. MicroRNAs and autophagy: fine players in the control of chondrocyte homeostatic activities in osteoarthritis. Oxidative Medicine and Cellular Longevity. 2017;2017:16. doi: 10.1155/2017/3720128.3720128
    1. Garofalo M., Condorelli G., Croce C. MicroRNAs in diseases and drug response. Current Opinion in Pharmacology. 2008;8(5):661–667. doi: 10.1016/j.coph.2008.06.005.
    1. Kode J. A., Mukherjee S., Joglekar M. V., Hardikar A. A. Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy. 2009;11(4):377–391. doi: 10.1080/14653240903080367.
    1. Kim C., Keating A. Cell therapy for knee osteoarthritis: mesenchymal stromal cells. Gerontology. 2019;65(3):294–298. doi: 10.1159/000496605.
    1. Al-Najar M., Khalil H., Al-Ajlouni J., et al. Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study. Journal of Orthopaedic Surgery. 2017;12(1):p. 190. doi: 10.1186/s13018-017-0689-6.
    1. 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. doi: 10.1016/j.biomaterials.2019.03.022.
    1. Wang R., Xu B., Xu H. TGF-beta1 promoted chondrocyte proliferation by regulating Sp1 through MSC-exosomes derived miR-135b. Cell Cycle. 2018;17(24) doi: 10.1080/15384101.2018.1556063.
    1. Mao G., Zhang Z., Hu S., et al. Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Research & Therapy. 2018;9(1):p. 247. doi: 10.1186/s13287-018-1004-0.
    1. Tao S.-C., Yuan T., Zhang Y.-L., Yin W.-J., Guo S.-C., Zhang C.-Q. 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(1):180–195. doi: 10.7150/thno.17133.
    1. Kopp F., Mendell J. T. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172(3):393–407. doi: 10.1016/j.cell.2018.01.011.
    1. Chen L.-L. Linking long noncoding RNA localization and function. Trends in Biochemical Sciences. 2016;41(9):761–772. doi: 10.1016/j.tibs.2016.07.003.
    1. Hung T., Wang Y., Lin M. F., et al. Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters. Nature Genetics. 2011;43(7):621–629. doi: 10.1038/ng.848.
    1. Fatica A., Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nature Reviews Genetics. 2014;15(1):7–21. doi: 10.1038/nrg3606.
    1. Ju C., Liu R., Zhang Y.-W., et al. Mesenchymal stem cell-associated lncRNA in osteogenic differentiation. Biomedicine & Pharmacotherapy. 2019;115 doi: 10.1016/j.biopha.2019.108912.108912
    1. Jiang S.-D., Lu J., Deng Z.-H., Li Y.-S., Lei G.-H. Long noncoding RNAs in osteoarthritis. Joint Bone Spine. 2017;84(5):553–556. doi: 10.1016/j.jbspin.2016.09.006.
    1. Cen X., Huang X. Q., Sun W. T., Liu Q., Liu J. Long noncoding RNAs: a new regulatory code in osteoarthritis. American Journal of Translational Research. 2017;9(11):4747–4755.
    1. Zhang S., Chu W. C., Lai R. C., Lim S. K., Hui J. H. P., Toh W. S. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis and Cartilage. 2016;24(12):2135–2140. doi: 10.1016/j.joca.2016.06.022.
    1. Qi X., Zhang J., Yuan H., et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. International Journal of Biological Sciences. 2016;12(7):836–849. doi: 10.7150/ijbs.14809.
    1. Liu 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):2411–2422. doi: 10.1080/15384101.2018.1526603.
    1. Zhao Y., Xu J. Synovial fluid-derived exosomal lncRNA PCGEM1 as biomarker for the different stages of osteoarthritis. International Orthopaedics. 2018;42(12):2865–2872. doi: 10.1007/s00264-018-4093-6.
    1. Greene M. A., Loeser R. F. Aging-related inflammation in osteoarthritis. Osteoarthritis and Cartilage. 2015;23(11):1966–1971. doi: 10.1016/j.joca.2015.01.008.
    1. Price J. S., Waters J. G., Darrah C., et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell. 2002;1(1):57–65. doi: 10.1046/j.1474-9728.2002.00008.x.
    1. Itahana K., Campisi J., Dimri G. P. Mechanisms of cellular senescence in human and mouse cells. Biogerontology. 2004;5(1):1–10. doi: 10.1023/b:bgen.0000017682.96395.10.
    1. Tofino-Vian M., Guillén M. I., del Caz M. D. P., Tofino-Castejón M. A., Alcaraz M. J. Extracellular vesicles from adipose-derived mesenchymal stem cells downregulate senescence features in osteoarthritic osteoblasts. Oxidative Medicine and Cellular Longevity. 2017;2017:12. doi: 10.1155/2017/7197598.7197598
    1. Zhang S., Teo K. Y. W., Chuah S. J., Lai R. C., Lim S. K., Toh W. S. MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis. Biomaterials. 2019;200:35–47. doi: 10.1016/j.biomaterials.2019.02.006.
    1. Zhu Y., Wang Y., Zhao B., et al. 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 Research & Therapy. 2017;8(1):p. 64. doi: 10.1186/s13287-017-0510-9.
    1. Scanzello C. R., Goldring S. R. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51(2):249–257. doi: 10.1016/j.bone.2012.02.012.
    1. Bonnet C. S., Walsh D. A. Osteoarthritis, angiogenesis and inflammation. Rheumatology. 2005;44(1):7–16. doi: 10.1093/rheumatology/keh344.
    1. Domenis R., Zanutel R., Caponnetto F., et al. Characterization of the proinflammatory profile of synovial fluid-derived exosomes of patients with osteoarthritis. Mediators of Inflammation. 2017;2017:11. doi: 10.1155/2017/4814987.4814987
    1. Goldring M. B., Otero M. Inflammation in osteoarthritis. Current Opinion in Rheumatology. 2011;23(5):471–478. doi: 10.1097/bor.0b013e328349c2b1.
    1. Zorzopulos J., Opal S. M., Hernando-Insúa A., et al. Immunomodulatory oligonucleotide IMT504: effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World Journal of Stem Cells. 2017;9(3):45–67. doi: 10.4252/wjsc.v9.i3.45.
    1. Hu H., Zou C. Mesenchymal stem cells in renal ischemia-reperfusion injury: biological and therapeutic perspectives. Current Stem Cell Research & Therapy. 2017;12(3):183–187. doi: 10.2174/1574888x11666161024143640.
    1. McGonagle D., Baboolal T. G., Jones E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nature Reviews Rheumatology. 2017;13(12):719–730. doi: 10.1038/nrrheum.2017.182.
    1. Mora A. L., Rojas M. Adult stem cells for chronic lung diseases. Respirology. 2013;18(7):1041–1046. doi: 10.1111/resp.12112.
    1. Rosset P., Deschaseaux F., Layrolle P. Cell therapy for bone repair. Orthopaedics & Traumatology: Surgery & Research. 2014;100(1):S107–S112. doi: 10.1016/j.otsr.2013.11.010.
    1. Xiao J., Yang R., Biswas S., Qin X., Zhang M., Deng W. Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis. International Journal of Molecular Sciences. 2015;16(5):9283–9302. doi: 10.3390/ijms16059283.
    1. Xu B., Luo Y., Liu Y., Li B.-Y., Wang Y. Platelet-derived growth factor-BB enhances MSC-mediated cardioprotection via suppression of miR-320 expression. American Journal of Physiology-Heart and Circulatory Physiology. 2015;308(9):H980–H989. doi: 10.1152/ajpheart.00737.2014.
    1. Gao K., Zhu W., Li H., et al. Association between cytokines and exosomes in synovial fluid of individuals with knee osteoarthritis. Modern Rheumatology. 2019:1–7. doi: 10.1080/14397595.2019.1651445.
    1. Lee W. S., Kim H. J., Kim K. I., Kim G. B., Jin W. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. STEM CELLS Translational Medicine. 2019;8(6):504–511. doi: 10.1002/sctm.18-0122.
    1. Okano H., Nakamura M., Yoshida K., et al. Steps toward safe cell therapy using induced pluripotent stem cells. Circulation Research. 2013;112(3):523–533. doi: 10.1161/circresaha.111.256149.
    1. Lai R. C., Yeo R. W. Y., Lim S. K. Mesenchymal stem cell exosomes. Seminars in Cell & Developmental Biology. 2015;40:82–88. doi: 10.1016/j.semcdb.2015.03.001.
    1. Aliotta J. M., Pereira N., Li M., et al. Stable cell fate changes in marrow cells induced by lung-derived microvesicles. Journal of Extracellular Vesicles. 2012;1(1) doi: 10.3402/jev.v1i0.18163.18163

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever