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Li, Z. Exosomes in Osteoarthritis. Encyclopedia. Available online: https://encyclopedia.pub/entry/20290 (accessed on 16 June 2024).
Li Z. Exosomes in Osteoarthritis. Encyclopedia. Available at: https://encyclopedia.pub/entry/20290. Accessed June 16, 2024.
Li, Zhong. "Exosomes in Osteoarthritis" Encyclopedia, https://encyclopedia.pub/entry/20290 (accessed June 16, 2024).
Li, Z. (2022, March 07). Exosomes in Osteoarthritis. In Encyclopedia. https://encyclopedia.pub/entry/20290
Li, Zhong. "Exosomes in Osteoarthritis." Encyclopedia. Web. 07 March, 2022.
Exosomes in Osteoarthritis
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Osteoarthritis (OA) is a prevalent and debilitating age-related joint disease characterized by articular cartilage degeneration, synovial membrane inflammation, osteophyte formation, as well as subchondral bone sclerosis. OA drugs at present are mainly palliative and do not halt or reverse disease progression. Currently, no disease-modifying OA drugs (DMOADs) are available and total joint arthroplasty remains a last resort. Exosomes are a type of extracellular vesicles (EVs) with a diameter ranging between 30 and 150 nm, and a density of 1.13–1.19 g/mL. These extracellular membrane-bound vesicles are able to work as cell-specific cargoes, which contain complex signaling molecules such as lipids, proteins, metabolites, nucleic acids, and cytosolic and cell-surface proteins.

osteoarthritis exosome extracellular vesicle regenerative medicine

1. Introduction

Osteoarthritis (OA) is the most common form of arthritis, causing chronic joint pain, decline in joint function, physical disability, and impaired quality of life in the affected population [1]. According to data from the National Health Interview Survey (NHIS), doctor-diagnosed OA and other forms of arthritis affected 52.5 million American adults during 2011–2012, and by 2040, this number is expected to be increased by 49% [2], creating a considerable socioeconomic burden [3]. During OA progression, pathological changes have been reported to affect the whole joint, including cartilage degradation, osteophyte formation, abnormal subchondral bone remodeling, synovitis, meniscus and ligament degeneration, hypertrophy of the joint capsule, and increased vascularization, inflammatory infiltration, and fibrosis in the infrapatellar fat pad (IPFP) [4][5]. Risk factors of OA, including age, gender, genetic predisposition, obesity, inflammation, and excessive mechanical loading, increases the probability of OA occurrence and development [6]. With the combined effects of aging, obesity, and an increasing number of joint injuries in the global population, this burdensome syndrome is expected to become more prevalent [7].
Treatment strategies of OA are limited due to the lack of knowledge about OA pathogenesis. At present, no disease-modifying osteoarthritis drugs (DMOADs) are available to reverse or halt OA progression [8]. Pharmacological approaches, such as the use of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and surgical interventions are current options to offer symptomatic relief [9]. However, these options are ineffective in repairing damaged articular cartilage, and are also challenged by relatively small effect sizes and uncertainty about their long-term efficacy and safety. These limitations hinder their clinical applications [10]. Considering that OA is a multifactorial disease with complex comorbid conditions, personalized treatment is essential to optimize outcomes [11]. To achieve this, researchers focus on developing personalized in situ intra-articular (IA) therapeutic options. IA drug delivery is superior to systemic administration with higher levels of efficacy and a lower risk of side effects. Different drug delivery systems have emerged to improve the local delivery of small molecules to joints [12]. Among them, exosomes, as a novel bio-cargo, have attracted significant attention in recent years.
Exosomes are a type of extracellular vehicles (EVs) with a diameter ranging between 30 and 150 nm, and a density of 1.13–1.19 g/mL [13]. These extracellular membrane-bound vesicles are able to work as cell-specific cargoes, which contain complex signaling molecules such as lipids, proteins, metabolites, nucleic acids, and cytosolic and cell-surface proteins [13]. Exosomes functions to mediate intercellular communications, and can be released into the extracellular environment by almost all types of cells through fusing plasma membrane and multivesicular bodies (MVBs) [14]. The biomedical applications of exosomes have been rapidly expanding in recent years because of their active roles in the function and pathophysiology of various body systems and potential in clinical therapeutics and diagnosis [15]. Diverse therapeutic payloads, such as DNAs, RNAs, antisense oligonucleotides, metabolites, chemotherapeutic agents, cytokines, and immune modulators, can be delivered to a target by engineered exosomes [16]. In OA related research, exosomes from multiple origins in the joint, such as tissue-specific mesenchymal stem cells (MSCs), chondrocytes, synovial fibroblasts (SFBs), osteoblasts, tenocytes, IPFP adipocytes, and platelet-rich plasma (PRP), have been detected and change with OA progression [17][18][19] (Figure 1).
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Figure 1. Tissue sources of exosomes in the knee joint. Exosomes are secreted by multiple types of cells of the joint, including adipocytes, adipose-derived stem cells (ADSCs), synovium-derived mesenchymal stem cells (MSCs), synovial fibroblasts and macrophages, chondrocytes, osteoblasts and osteocytes in the subchondral bone, vascular endothelial cells, immune cells such as T cells, B cells, and dendritic cells (DCs) meniscus cells, periodontal ligament cells, tenocytes, tendon stem cells, and bone marrow-derived MSCs. These exosomes are involved in the regulation of joint homeostasis, cell–cell communications, and the initiation and progression of OA.

2. Formation and Origin of Exosomes

The concept of ‘exosomes’ was first proposed in 1981 by Trams et al. [20]. In 1983, the currently defined exosomes were first identified in sheep reticulocytes and named by Johnstone et al. [21]. However, the widespread clinical applications were limited by the low yield for the production method used and unexpected therapeutic effects [22]. Besides, the function of exosomes is dependent on both the type and condition of the cells that they are released from, and thus varies a lot. To optimize the application, a comprehensive understanding of the generation, origins, and contents of exosomes is required.

2.1. Biogenesis of Exosomes

The detailed biological synthesis process of exosomes is shown in Figure 2. The cellular biogenesis process of exosomes begins with double invagination of the plasma membrane [23]. This is followed by the accumulation of bioactive substances in the early sorting endosomes (ESEs), such as lipids, proteins, small molecules, ions, and metabolites present in the extracellular space. The ESEs subsequently mature into late sorting endosomes (LSEs), a process regulated by endosomal sorting complex required for transport (ESCRT) proteins and others. After that, invagination of the limiting membrane of LSEs results in the formation of MVBs (also referred to as multivesicular endosomes) [16]. The MVBs can be degraded by fusing with autophagosomes or lysosomes; alternatively, MVBs fuse with the plasma membrane and release exosomes—vesicles containing the intra-endosome substances—to the extracellular space [23].
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Figure 2. Scheme of the biogenesis of exosomes. Endocytosis and plasma membrane invagination facilitate the entry of cell surface proteins and extracellular components such as lipids, proteins, metabolites, ions, and small molecules into cells, leading to the formation of early sorting exosomes (ESEs). The ESEs then fuse with the endoplasmic reticulum (ER) and/or trans-Golgi network (TGN) and result in late sorting exosome (LSE) formation. A second invagination in the LSEs leads to the generation of multivesicular bodies (MVBs). MVBs can then either fuse with lysosomes for degradation or be transported to the plasma membrane and undergo exocytosis—a process resulting in exosome release. Exosomes, filled with various cellular components such as proteins, mRNAs, miRNAs, lipids, enzymes, and carbohydrates, are released through exocytosis after MVBs fuse with the cell membrane. Released exosomes can be further taken up by adjacent or remote cells in various ways, including receptor-mediated endocytosis and fusion with the plasma membrane of cells.
A key component of OA treatment is the efficient delivery of therapeutic molecules to targeted cells, especially to chondrocytes embedded in a dense extracellular matrix (ECM), which requires the use of biocompatible molecular transport vehicles. Exosomes exhibit unique features, such as high serum stability and strong penetration across biological barriers, which make them ideal cargoes for drug delivery in OA treatment [24]. However, pristine exosomes can experience fast clearance in the body and have weak cell-targeting abilities, resulting in unsatisfactory treatment outcomes. Therefore, bioengineered exosome-mediated delivery strategies, such as drug loading and surface modifications, have been explored to improve the cell-targeting property of exosomes [23]. For example, genetic engineering methods have been utilized to introduce specific proteins, such as ligands for receptors or antibodies against target cells, to the surface of exosomes to achieve precise delivery [25].

2.2. Origins of Exosomes and Their Roles in OA

Osteoarthritis is a whole-joint disease with pathological changes observed in all joint components [26]. Exosomes secreted by cells in joint tissues or from IA-injected therapeutic agents exhibit complex regulatory effects on the progression of OA [27]. MSCs, derived from tissues within the joint (e.g., subchondral bone, IPFP, and synovium) and elsewhere, represent the most widely studied sources of exosome production. In addition, exosomes have also been obtained from non-classic sources including, but not limited to, articular chondrocytes, adipocytes, osteoblasts, osteocytes, vascular endothelial cells, and PRP [28]. Exosomes derived from different origins exhibit varying effects. Some exosomes showed chondroprotective effects, while others, such as vascular endothelial cell (VEC) and OA chondrocyte-derived exomes, promoted OA progression. Detailed information and potential regulatory mechanisms of exosomes generated by different cells are listed in Table 1. In this section, the different exosome sources are discussed, with an emphasis on joint-related tissues and cells, followed by a description of their roles in OA.
Table 1. Summary of major findings of OA-related studies involving the use of exosomes.
Cells Source Extraction Dose Delivery Method Target Cells Results Ref
VECs Conditioned medium Ultrafiltration 100 μg Co-incubation for 24 h Primary chondrocytes Promoted OA progression by inhibiting chondrocyte autophagy, downregulating p21 expression, and increasing ROS production and apoptosis. [29]
OA chondrocytes Culture supernatant Ultracentrifugation 1 × 106/mL Co-incubation Synovial macrophages Promoted OA progression by stimulating inflammasome activation and upregulating mature IL-1β production in synovial macrophages [30]
Primary chondrocytes Conditioned medium Ultracentrifugation 200 μg/mL Co-incubation for 48 h
Intra-articular injection
Chondrocytes Prevented OA via the restoration of mitochondrial function and macrophage polarization toward the M2 phenotype [31]
OA osteoblasts Conditioned medium Ultracentrifugation 20 μg/mL Co-incubation for 14 d Chondrocytes Promoted OA progression by suppressing oxygen consumption by chondrocytes via miR-210-5p. [32]
BM-MSCs Conditioned medium Ultracentrifugation 10 μg/mL Co-incubation for 24 h Chondrocytes Promoted proliferation and inhibited apoptosis of chondrocyte via miR-206/GIT1 axis [33][34]
BM-MSCs Conditioned medium Ultracentrifugation 250 ng Intra-articular injection Chondrocytes Prevented OA development by inhibiting the degradation of cartilage and the formation of osteophyte [35]
BM-MSCs Conditioned medium Ultracentrifugation 200 μg/mL 3D printed ECM/GelMA/exosome scaffolds Osteochondral defect rabbit model Prevented OA development by facilitating cartilage regeneration and restoring chondrocyte mitochondrial function [36]
SMSCs Conditioned medium Ultracentrifugation 5 μg Co-incubation for 12 h Chondrocytes Prevented the development of OA by facilitating migration, proliferation and ECM secretion and suppressing chondrocyte apoptosis [37]
SMSCs Conditioned medium Ultracentrifugation 1010 particles Intra-articular injection DMM mice model Prevented OA development by enhancing cartilage tissue regeneration via miR-140-5p upregulation of Wnt and YAP [38]
ESC-MSCs Conditioned medium Ultrafiltration 5 μg/mL
100 μg
Co-incubation for 48 h
Intra-articular injection
TMJ condylar chondrocytes Prevented OA development via inflammation attenuation and matrix homeostasis restoration [39]
ESC-MSCs Conditioned medium Ultracentrifugation 881 ng Intra-articular injection DMM OA model Prevented OA development by balancing cartilage ECM synthesis and degradation [40]
iPSC-MSCs Conditioned medium Ultracentrifugation 8 μL
1010/mL
Intra-articular injection Collagenase-induced OA model Prevented OA development by promoting migration and proliferation of chondrocytes [41]
UC-MSCs Conditioned medium Ultracentrifugation 10 μg/mL
100 μg
Co-incubation for 72 h
Intra-articular injection
Rat cartilage defect model Mechanical stimulation increased the expression level of LncRNA H19 in exosomes, which promoted chondrocyte proliferation, matrix synthesis, and inhibited apoptosis [42]
ADSCs Conditioned medium Ultracentrifugation 400 µg/mL Co-incubation for 48 h Chondrocytes Prevented OA development by promoting chondrogenesis and suppressing inflammation via upregulating miR-221 and miR-145 [43]
ADSCs Conditioned medium Ultracentrifugation 108 particles Intra-articular injection DMM and MIA induced OA model Prevented OA development by inhibiting proteoglycan degradation and cartilage destruction and ameliorating gait abnormality [44][45]
AFSC Conditioned medium Precipitation 30 μg
100 μg
Co-incubation for 72 h
Intra-articular injection
MIA-induced OA mice model Prevent the development of OA by promoting chondrocyte proliferation, cartilage matrix synthesis, and polarizing macrophages to M2 phenotype [46]
Engineered CAP-Lamp2b exosomes Conditioned medium Ultracentrifugation 10 μg
100 μg
Co-incubation for 3 h
Intra-articular injection
Chondrocytes
DMM OA rat model
Prevented OA development by delivering miR-140 to deep cartilage regions and inhibiting cartilage-degrading proteases [47]
CPCs Conditioned medium Ultracentrifugation 108/mL
8 × 107 particle
Co-incubation for 3 h
Intra-articular injection
Chondrocytes Enhanced articular cartilage repair by stimulating chondrocyte proliferation and migration via upregulating miRNA 221-3p [48]
Synoviocytes Conditioned medium Ultracentrifugation 20 μg/mL Co-incubation for 24 h Chondrocytes Promoted OA progression by inducing apoptosis and cartilage matrix degradation via upregulating miR-142-5p/RUNX2 [49]
Synovial fibroblasts Patient synovial fluid Ultracentrifugation 2 × 109/mL
20 μg
Co-incubation for 48 h
Intra-articular injection
ACLT  +  MMx OA rat model Prevented OA development by suppressing chondrocyte apoptosis, constraining inflammation, and cartilage degeneration [50]
PRP PRP exoEasy Maxi Kit 50 μg/mL
100 μg/mL
Co-incubation for 24 h
Intra-articular injection
Chondrocytes Prevented OA development by facilitating proliferation and reducing apoptosis of chondrocyte via Wnt/β-catenin [17]
CPRP Whole blood Ultracentrifugation 1.42 × 109 particles Co-incubation for 48 h OA chondrocytes Prevented OA development by inducing chondrogenic gene expression changes and preventing proinflammatory cytokine release [51]
IPFP IPFP Ultracentrifugation 10 μL
1010/mL
Intra-articular injection DMM mice model Prevented OA development by alleviating articular cartilage damage via miR-100-5p downregulation of mTOR [44]
Tenocyte Conditioned medium Ultracentrifugation 486.3 μg/mL Co-incubation for 48 h Tendon stem cells Promoted tendon healing by regulating tendon ECM metabolism and inducing the tenogenic differentiation of MSCs via upregulating transforming growth factor-beta [52][53]
Periodontal ligament cells PureExo® exosome isolation kit Precipitation 5 μg/mL Co-incubation for 48 h Macrophage Regulated macrophage function and maintained inflammation homeostasis by suppressing IL-1β via inhibiting NF-κB signaling pathway [54]
LPS-pretreated PDLFs Conditioned medium Ultracentrifugation 100 μg/mL Co-incubation for 48 h Osteoblast Prevented bone remodeling by inducing inflammation and inhibiting osteogenic activity of osteoblasts, promoting macrophage polarization toward M1 via YAP [55][56]

VECs: vascular endothelial cell; BM-MSCs: bone marrow mesenchymal stem cells; ESC-MSCs: embryonic stem cell-derived MSCs; iPSC-MSCs: induced pluripotent stem cells-derived MSCs; UC-MSCs: umbilical cord mesenchymal stem cells; CPCs: chondrogenic progenitor cells; DMM: destabilization of the medial meniscus; ACLT + MMx: anterior cruciate ligament and resecting the medial menisci; PRP: platelet-rich plasma; CPRP: citrate-anticoagulated platelet-rich plasma; SMSCs: synovial mesenchymal stem cells; IPFP: infrapatellar fat pad; AFSC: amniotic fluid stem cells; ADSCs: adipose-derived stem cells; MIA: monosodium iodoacetate; PDLSCs: periodontal ligament-derived stem cells; PDLFs: periodontal ligament fibroblasts.

2.2.1. Exosomes Derived from Different Types of MSCs

MSCs possess multilineage differentiation potential and have been applied in IA injection therapies for OA treatment [57]. However, MSCs also face several limitations, including heterogeneity, inconsistent stemness, variable differentiation capacity, limited homing ability, and potential adverse effects, such as immune incompatibility, tumorigenicity, and chromosomal aberrations [58][59]. A growing body of evidence suggests that MSC-secreted exosomes should be credited for many of the previously reported regenerative properties of MSCs [60]. It was found that bone marrow MSC (BMSC)-derived exosomes can be endocytosed by chondrocytes. These exosomes showed capability in restoring the proliferation of chondrocytes, promoting ECM synthesis, and relieving knee OA pain [34]. Using MSC-derived exosomes to deliver mitochondrial-related proteins was reported to alleviate oxidative stress-induced damage and reverse mitochondrial dysfunction in degenerative OA cartilage [36]. MSC-derived exosomes containing a novel lncRNA KLF3-AS1 (KLF3 Antisense RNA 1; Ensembl: ENST00000440181) reversed the suppressive effects of miR-206 on the expression of G-protein-coupled receptor kinase interacting protein-1 (GIT1). It has been reported that GIT1 could promote the proliferation and inhibit the apoptosis of chondrocytes [61]. Thus, the lncRNA-KLF3-AS1/miR-206/GIT1 axis is possibly responsible for the chondroprotective effects of MSC-derived exosomes in OA [33].
In addition to BMSC, embryonic stem cell-derived MSCs (ESC-MSCs) [40], synovial MSCs (SMSC) [37][38], adipose-derived MSCs (ADSC) [21][62], umbilical cord mesenchymal stem cells (UC-MSCs) [42], periodontal ligament-derived stem cells (PDLSCs) [63], amniotic fluid stem cells (AFSCs) [46], and IPFP-MSCs [44][64][65] are other important origins of MSC-derived exosomes in OA treatment [38]. IA injection of ESC-MSC-derived exosomes facilitated the repair of osteochondral defects, maintained the chondrocyte phenotype, promoted cartilage formation, reduced matrix degradation, and impeded cartilage destruction both in vitro and in the destabilization of medial meniscus (DMM)-induced OA model in mice [40][66]. Mechanistically, these effects were achieved by promoting chondrocyte proliferation and migration, increasing collagen type II synthesis, and decreasing ADAMTS5 (A disintegrin and metalloproteinase with thrombospondin motifs 5) expression [40]. Exosomes obtained from miR-155-5p-overexpressing SMSC were used to treat OA chondrocytes and promoted their migration and proliferation, suppressed apoptosis, and enhanced the secretion of ECM; such exosomes also effectively prevented OA from occurring in mice undergoing cold water stimulation for 4 h/day over 20 days (which induced OA in the mice without exosome treatment) [37]. Recently, it was found that exosomes released by induced pluripotent stem cell (iPSC)-derived MSCs have a greater therapeutic effect compared with those from SMSCs [41]. IA injection of ADSC-derived exosomes showed an inhibitive effect on M1 macrophage infiltration into the synovium, significantly attenuating OA progression and preventing cartilage degeneration in both surgically induced (through DMM) mouse OA models and monosodium iodoacetate (MIA)-insulted rat joints [45]. Besides, ADSC-derived exosomes decreased the activity of senescence-related β-galactosidase in OA osteoblasts and the accumulation of γ H2AX foci, which were probably attributed to the protective effects on mitochondria [62]. Exosomes derived from UC-MSCs, which contained a high level of LncRNA H19, promoted chondrocyte proliferation and inhibited apoptosis in vitro; the exosomes also improved macroscopic assessment and relieved pain levels in a rat model of cartilage defect [42]. Furthermore, exosomes extracted from the conditioned medium of PDLSCs showed anti-inflammatory effects on chondrocytes, synoviocytes, and meniscus cells, mediating the inflammatory processes in various tissues in the joint [63]. AFSC-derived exosomes were found to increase pain tolerance and induce the restoration of hyaline cartilage with good surface regularity in an MIA-induced OA model [46]. An in vivo study showed that miR-100-5p-abundant IPFP-MSC-derived exosomes (IPFP-Exos) had chondroprotective effects and ameliorated gait abnormalities via inhibiting mTOR-autophagy pathway in an OA mouse model [44]. In vitro studies suggested that IPFP-Exos promoted chondrogenesis in periosteal cells via upregulating the expression of miR-221 and miR-145 and suppressing the production of proinflammatory cytokines [43]. Exosomes derived from kartogenin-pretreated IPFP-MSCs showed a stronger ability to induce stem cell chondrogenesis and promoted the proliferation of chondrocytes and the repair of articular cartilage defects both in vivo and in vitro [64]. Detailed information is summarized in Table 1.

2.2.2. Exosomes Derived from Chondrocytes and Chondrogenic Progenitor Cells

Exosomes released by chondrocytes participate in the pathologic mineralization of OA cartilage and cell–cell communication [67][68], affecting cartilage maintenance and OA pathogenesis [19]. These exosomes have dual roles in OA, depending on the cell condition and cell types. Exosomes from healthy chondrocytes had high bioactivity in the elimination of mitochondrial dysfunction and restoration of immune reaction by regulating M2 macrophage penetration, thus delaying OA progression [31]. These chondrocyte-derived exosomes contained miR-8485, which inhibited the expression of glycogen synthase kinase (GSK)-3β and activated the Wnt/β-catenin pathway, promoting the chondrogenic differentiation of BMSCs [69]. On the contrary, exosomes derived from OA chondrocytes enhanced chondrocyte apoptosis, inhibited cell proliferation, stimulated the activation of inflammasome, and upregulated the production of mature interleukin (IL)-1β in macrophages via promoting miR-449a-5p/ATG4B-mediated autophagy [30].
The chondrogenic progenitor cells (CPCs) are a type of resident cells in cartilage with high chondrogenic differentiation potential and a strong ability to self-renew and possess a regenerative ability in both diseased and healthy articular cartilage tissues [70]. CPC-derived exosomes enhanced the proliferation and migration of chondrocytes and alleviated OA in a DMM mouse model, probably via upregulating miRNA 221-3p [48].

2.2.3. Exosomes Derived from SFBs and Macrophages

Synoviocytes generally refer to SFBs and synovial macrophages, and SFBs are the major cell type in synovium [71]. Except for SMSC, SFBs and synovial macrophages also secret exosomes that regulate cartilage homeostasis and osteophyte formation [72]. Exosomes released by IL-1β treated SFB induced OA-like changes in articular chondrocytes by increasing the expression of catabolic genes, such as ADAMTS-5 and matrix metalloproteinases (MMP)-13, and downregulating the expression of anabolic genes, such as collagen type II (COL2) and aggrecan (ACAN) [71]. Exosomes from other synovial cells, including immune cells (e.g., macrophages, lymphocytes, and T cells) and endothelial cells, though not widely studied, are also believed to participate in the regulation of OA development [73]. Zeng et al. found that long non-coding RNA (lncRNA) prostate cancer gene expression marker 1 (PCGEM1) was overexpressed in exosomes from OA fibroblast-like synoviocytes (FLSs). FLS-derived exosomal PCGEM1 aggravated IL-1β-caused apoptosis and cartilage matrix degeneration in chondrocytes by sponging miR-142-5p and upregulating RUNX2 [49]. FLS-derived exosomal lncRNA H19 enhanced cell migration and proliferation, inhibited matrix degradation as well as alleviated OA progression by suppressing the miR-106b-5p/TIMP2 axis [74]. Though cytokines produced by macrophages and the imbalance between M1 and M2 macrophages are critical in OA pathogenesis, the effects of macrophage-derived exosomes on OA have been rarely studied thus far [75].

2.2.4. Exosomes Derived from Osteoblasts and Osteocytes

The remodeling of subchondral bone is a critical feature of OA and strongly associated with disease severity and joint pain in clinical OA patients [76]. Altered crosstalk between articular cartilage and the subchondral bone, which can be modulated by exosomes in OA progression, has attracted much attention but not been well studied. Wu et al. found that exosomes produced by osteoblasts in osteoarthritic, sclerotic subchondral bone contained a high level of miR-210-5p, which decreased the rate of oxygen consumption by chondrocytes, altered their bioenergetic state, and accelerated the progression of cartilage degeneration [32]. Exosome-like EVs have been extracted from osteoblasts harvested from OA subchondral bones. The OA osteoblast-derived exosomes were found to have upregulated expression of five miRNAs—hsa-miR-885-3p, hsamiR-4717-5p, hsamiR-210-5p, hsa-miR-135a-3p, and hsa-miR-1225-5p—than those obtained from the healthy controls; the physiological and pathological roles of these molecules still remain unclear [19].
Osteocytes release miRNA-containing exosomes, which deliver their components via blood circulation to the recipient cells to regulate biological processes [77]. In addition, osteocytes are sensitive to mechanical strains. Cultured under cyclic stretch of 8% shape variable at a frequency of 0.1 Hz for 30 min, osteocytes produce exosomes containing differentially expressed miRNAs compared with those from non-loading groups. These exosomes promoted the proliferation and osteogenesis of human PDLSCs by activating the miR-181b-5p/PTEN/AKT signaling pathway [78]. Myostatin, a myokine secreted by muscles, suppressed the expression of miR-218 in osteocyte-derived exosomes. Treated with these exosomes, osteoblasts showed decreased osteoblastic differentiation and down-regulated activity of the Wnt signaling pathway [79]. Osteocyte exosomes were also found to accelerate benign prostatic hyperplasia development by promoting cell proliferation [80].

2.2.5. Exosomes Derived from Adipose Tissue

IPFP is intraarticular adipose tissue that functions to reduce mechanical loading and absorb shock, and act as an abundant source of cytokines, lipid mediators as well as regenerative cells for cartilage repair [81]. IPFP is primarily comprised of adipocytes, and other cell types, including IPFP-derived MSCs and immune cells, are also found. As discussed earlier, intense interest has been spurred in IPFP-derived MSCs and IPFP-Exos [65].
Given the regulatory roles of adipose tissue in immune and nonimmune functions, compositional and functional analyses of adipocyte-derived exosomes can provide valuable information on the communications between adipocytes and other cells, such as immune cells, in the joint. A proteomic analysis of exosomes from obese diabetic and obese non-diabetic rats has been conducted. Among the 509 proteins identified, 200 of them were differentially expressed [82]. Sano et al. characterized the proteomic profiles of exosomes obtained from differentiated 3T3-L1 adipocytes and found that hypoxic culture upregulated the total protein amount in the exosomes and enriched the enzymes related to de novo lipogenesis [83]. According to Kita et al., adipose-derived exosomes can function as signaling packages and waste disposal bags [84]. Several lines of evidence support the role of adipose-derived exosomes in modulating macrophage polarization and hence inflammation [85][86][87]. Considering that obesity is a major risk factor for OA, investigations into adipose-derived exosomes may shed light onto molecular mechanisms underlying OA pathogenesis and the concurrent crosstalk between joint tissues.

2.2.6. Exosomes Derived from PRP

Blood-derived products, including plasma- and serum-based whole blood derivatives, have been applied to OA treatment via IA injection for years [88]. IA injection of PRP has been reported to promote the proliferation and differentiation of chondrocytes and facilitate matrix synthesis [89]. Three types of platelet granules have been defined: dense granules, α-granules, and lysosomes, and they differ in size, content, biomarker, synthesis process, and function [90]. Extracting exosomes from other types of granules is mainly based on size and specific membrane proteins [91]. Previous studies showed that exosomes originating from platelets were sufficient to enhance anabolic marker expression and prevent the release of proinflammatory cytokines in chondrocytes derived from OA patients, showing the same regulatory effects as the full blood product [51]. In addition, the therapeutic effects of PRP-derived exosomes in inhibiting apoptosis and promoting proliferation of chondrocytes were achieved by activating the Wnt/β-catenin signaling pathway [17]. The PRP-derived exosomes are relatively easy to prepare, do not require cell culture, and have minimal risks of disease transmission, making PRP-derived exosomes highly promising in OA treatment.

2.2.7. Exosomes Derived from Other Cells

Exosomes derived from vascular endothelial cells (EC-Exos) were found to promote the progression of OA; EC-Exos increased the susceptibility of mouse chondrocytes to anoxidative stress by inhibiting p21 expression and autophagy, leading to more apoptotic chondrocytes in the mouse OA model [29]. The serum of OA patients was found to have elevated levels of T cell-derived, CD3- and CD4-positive exosomes, and platelet-derived EVs positive for annexin V and CD61+ and negative for CD45, as compared to that of healthy controls [92][93]. Exosomes from immune cells, such as B cells, T cells, and dendritic cells, caused the production of several cartilage-degrading enzymes (including MMP-1, MMP-3, MMP-9, and MMP-13) and inflammatory cytokines and chemokines (including IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, and MCP-2) in SFBs from OA patients [94][95][96][97]. Exosomes from tenocytes were found to facilitate the tenogenic differentiation of MSCs, promoting the healing of injured tendons and increasing the maximum loading and ultimate stress in tendons [53]. Cyclic stretch force-induced PDL cells secreted exosomes that suppressed the production of IL-1β by inhibiting the NF-κB pathway in macrophages [54]. Human PDL fibroblast (hPDLFs)-derived exosomes induced inflammation and inhibited osteogenesis by osteoblasts [55]. Static compressive force stimulated the production of exosomes in PDLFs. These exosomes, containing a high level of the Yes-associated protein (YAP), promoted macrophage polarization toward the M1 phenotype [56]. Research on exosomes derived from these cells is just the beginning. More research is needed on their roles in OA pathogenesis and treatment.

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