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Review
. 2022 Oct 20:22:423-452.
doi: 10.1016/j.bioactmat.2022.10.012. eCollection 2023 Apr.

Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis

Zichang Liu  1   2 , Yu Zhuang  1   3 , Lianfei Fang  2 , Changyong Yuan  4 , Xudong Wang  1 , Kaili Lin  1
Affiliations
Review

Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis

Zichang Liu et al. Bioact Mater. .

Abstract

Osteoarthritis (OA) is a highly prevalent whole-joint disease that causes disability and pain and affects a patient's quality of life. However, currently, there is a lack of effective early diagnosis and treatment. Although stem cells can promote cartilage repair and treat OA, problems such as immune rejection and tumorigenicity persist. Extracellular vesicles (EVs) can transmit genetic information from donor cells and mediate intercellular communication, which is considered a functional paracrine factor of stem cells. Increasing evidences suggest that EVs may play an essential and complex role in the pathogenesis, diagnosis, and treatment of OA. Here, we introduced the role of EVs in OA progression by influencing inflammation, metabolism, and aging. Next, we discussed EVs from the blood, synovial fluid, and joint-related cells for diagnosis. Moreover, we outlined the potential of modified and unmodified EVs and their combination with biomaterials for OA therapy. Finally, we discuss the deficiencies and put forward the prospects and challenges related to the application of EVs in the field of OA.

Keywords: Biomarkers; Diagnosis; Extracellular vesicles; Osteoarthritis; Treatment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Key events of EVs in the pathogenesis, diagnosis, and treatment of OA. Red: Typical examples of EVs in pathogenesis research. Purple: The signature events of EVs as markers for diagnosis and differential diagnosis. Blue: The therapeutic roles of EVs from different sources through different mechanisms, and all known modification strategies, as well as typical biomaterials for loading EVs.
Fig. 2
Fig. 2
EVs in the pathogenesis, diagnosis, and treatment of osteoarthritis.
Fig. 3
Fig. 3
EVs from different cells exacerbates the inflammation of osteoarthritis: (A) EVs from SF and chondrocytes affect macrophages, leading to the intensification of synovial inflammation. (B) EVs from the joint microenvironment affect chondrocyte metabolism, leading to increased catabolism and cartilage matrix destruction. (C) EVs from osteoclasts cause abnormal subchondral bone remodeling.
Fig. 4
Fig. 4
Roles of EVs in the cell senescence: (A) Age-related EVs lead to the formation and spread of inflammation. (B) EVs from SnCs induce aging of nearby cells, including loss of normal function and increase of cell senescence.
Fig. 5
Fig. 5
Roles of EVs in mitochondrial damage and oxidative stress. In the pathological state of chondrocytes, oxidative phosphorylation decreases and glycolysis increases, leading to mitochondrial dysfunction and oxidative stress. The role of EVs in this change can be divided into two modes. First, EVs from cartilage and endothelial cells carry endogenous substances to accelerate ROS accumulation and enhance chondrocyte metabolic disorder. Second, EVs in the state of oxidative stress carry a lot of pathological contents, which aggravate the progression of OA.
Fig. 6
Fig. 6
EVs from different sources loaded with different cargoes plays different roles in the diagnosis of OA.
Fig. 7
Fig. 7
EVs from various sources without modification for OA therapy. Abbreviation: BMSCs, Bone marrow mesenchymal stem cells; ADSCs, adipose mesenchymal stem cells; SMSCs, synovial mesenchymal stem cells; EMSCs, embryonic mesenchymal stem cells; UMSCs, umbilical cord mesenchymal stem cells; AMSCs, amniotic mesenchymal stromal cells; AFSCs, amniotic fluid stem cells; SHED, stem cells from human exfoliated deciduous teeth; CPCs, chondrogenic progenitor cells; SFB, synovial fibroblasts; hypACT, hyperacute serum; PRP, platelet-rich plasma; SECMs, sea cucumber extracellular matrices; ASCs, antler stem cells.
Fig. 8
Fig. 8
BMSCs-Exos relieved cartilage damage and pain in OA rats. (A) Western blot analysis of COL2A1 and MMP13 protein levels (* compared with the control group, # compared with the IL-1β group). (B) In vivo imaging after intra-articular injection of exosome (Fluo, Fluorescence, BF, brightfield). (C) General morphology of the knee joint in rats. (D) Saffron solid green staining of the knee joint (scale = 50 μm). (E) OARSI scores among different groups. (F) ELISA of inflammatory factors in cartilage. (* compared with Sham group, # compared with OA group, n = 8 for each group). (G) PWT and PWL of rats at different time. (H) Immunofluorescence staining of CGRP and iNOS proteins in DRG tissues (scale = 200 μm, * compared with Sham group, # compared with OA group, n = 4 for each group). (I) A model of knee OA induced pain in rats. Reproduced under the terms of the CC-BY 4.0 [144]. Copyright 2020, The Authors, published by Springer Nature.
Fig. 9
Fig. 9
EMSC-Exos relieved osteoarthritis by reducing inflammation, inhibiting pain, and restoring matrix homeostasis. (A) The mechanism of EMSC-Exos promoting joint repair. (B) Time-dependent injury response after treatment indicated the effect of Exos treatment on pain. (C) Exos treatment suppressed inflammation. Expression of IL-1β+ cells in cartilage at 2, 4, and 8 weeks. (D) Exos treatment reduced apoptosis. Expression of CCP3+ cells in cartilage at 2, 4, and 8 weeks. (E) Exos reversed TMJ degeneration in OA patients. Schematic model of joint condyle head (left), condyle height in different areas (upper right), percentage of cartilage thickness in different areas (lower right). * Compared to OA + PBS group, # compared to Sham group, n = 6–8/group. Reproduced with permission [161]. Copyright 2019, Elsevier.
Fig. 10
Fig. 10
ASC-Exos alleviate MSCs senescence and osteoarthritis. (A) Schematic diagram of ASC-Exos restoring stem cell senescence in vitro and alleviating OA progression in vivo. (B) hMSCs were treated with vector (Veh) or exosome (Exo) for SA-β-Gal staining (scale, 50 μm), and quantification. Western blot and quantification of P16 and P21 expression. Heat map of relative mRNA expression levels of SASP-related genes (n = 3). (C) Bone mineral density analysis of joints of OA mice treated with Veh or Exo (n = 15). (D) Saffron solid green staining (scale, 200 μm) and OARSI grade of articular cartilages (n = 15). (E) Immunohistochemical staining (scale, 60 μm) of Ki67 and P16 and quantitative analysis of articular cartilage in OA mice treated with Veh or Exo (n = 15). (F) Venn diagram showing the number of differentially expressed genes in OA mice after Exo treatment. Reproduced under the terms of the CC-BY 4.0 [26]. Copyright 2022, The Authors, published by Springer Nature.
Fig. 11
Fig. 11
Main strategies for EVs modification. Left: Strategies for modifying donor cells. Co-incubation, transfection and hypoxia are biochemical factors, which are used to load cargoes into donor cells. Mechanical stress and 3D-culture are mechanical factors that increase yield and change contents. Right: Strategies for directly modifying EVs. Direct mixing and electroporation are used to introduce cargoes into EVs. Fusion with membrane proteins and reverse surface charge are used to modify EVs membrane to improve targeting, distribution, retention, and bioavailability. Nanomaterials including liposomes can be mixed with EV membranes to generate hybrid EVs.
Fig. 12
Fig. 12
Co-incubation as a modification strategy of donor cells. (A) Pattern diagram of Cur-EVs reversing IL-1β induced catabolism of OA-CH. (B) qRT-PCR analysis of the effect of Cur-EVs on OA-CH gene expression. n = 4; * compared with the control group; # difference between groups. C. Effects of Cur-EVs on expression of miR-126-3p gene in OA-CH. Reproduced under the terms of the CC-BY 4.0 [220]. Copyright 2021, The Authors, published by Springer Nature.
Fig. 13
Fig. 13
Gene transfection as a modification strategy of donor cells. (A) Pattern diagram of H19-Exos playing a protective role in cartilage. (B) Quantitative analysis of SA-β-Gal staining of chondrocytes and protein and mRNA levels of chondrocyte-associated genes. (C, D) Gross, MRI images and International Cartilage Repair Society (ICRS) score of regenerated tissues at weeks of 4 and 8, (n = 5). (E, F) Histological staining and Wakitani score after 4 weeks of cartilage repair (n = 5). Reproduced under the terms of the CC-BY 4.0 [29]. Copyright 2021, The Authors, published by Wiley-VCH.
Fig. 14
Fig. 14
Modifications of EVs membrane. Left: E7-Exos delivered KGN to SFSCs to enhance cartilage regeneration. Right: PPD-sEVs reversed the surface charge and enhanced OA treatment. (A) Diagram of exosome engineering to enhance the delivery of KGN to SFSCs, and for cartilage regeneration. (B) Fluorescence images show that KGN was selectively delivered to SFSCs instead of chondrocytes (n = 3), scale bar = 10 μm. (C) Typical microscopic images of cartilage tissues in different treatment groups by HE staining and SO-FG staining. Reproduced with permission [30]. Copyright 2021, Elsevier. (D) Schematic diagram of sEVs reverse surface charge modification strategy by PPD. (E) DiO (green) labeled sEVs or PPD-sEVs chondrocyte uptake, scale bar = 50 μm. (F) Positive chondrocyte rate for uptake of DiO labeled sEVs or PPD-sEVs. (G) Cartilage degradation assessed by H&E and SO-FG staining, scale bar = 200 μm; Reproduced under the terms of the CC-BY 4.0 [32]. Copyright 2021, The Authors, published by Wiley-VCH.
Fig. 15
Fig. 15
Generating biomimetic EVs containing Cas9 sgMMP-13. (A) Schematic diagram of chondrocyte specific gene editing by hybrid CAP-Exo construction. (B) TEM images of CAP-Exo, liposomes, and hybrid CAP-Exo. Scale bar: 200 nm. (C) Schematic image of the Cas9 sgMMP-13 system, and detection of MMP-13 mRNA levels by qRT-PCR in chondrocytes co-incubated with Cas9 sgMMP-13 loaded in different forms. (D) Schematic diagram of intra-articular injection and chondrocyte uptake of Hybrid CAP-Exo, and distribution of Hybrid Exo and Hybrid CAP-Exo in vivo. (E) Schematic illustration of the in vivo procedure and modified OARSI score of cartilage tissue after four weeks. (F) Quantification of fluorescence signals of MMP-13, Aggrecan, and Collagen II in different treatment groups after four weeks. Reproduced under the terms of the CC-BY 4.0 [31]. Copyright 2022, The Authors, published by IVYSPRING INT PUBL.
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