Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis

Abstract

Osteoarthritis (OA) and rheumatoid arthritis (RA) are both debilitating diseases that cause significant morbidity in the US population. Extracellular vesicles (EVs), including exosomes and microvesicles, are now recognized to play important roles in cell-to-cell communication by transporting various proteins, microRNAs (miRNAs), and mRNAs. EV-derived proteins and miRNAs impact cell viability and cell differentiation, and are likely to play a prominent role in the pathophysiology of both OA and RA. Some of the processes by which these membrane-bound vesicles can alter joint tissue include extracellular matrix degradation, cell-to-cell communication, modulation of inflammation, angiogenesis, and antigen presentation. For example, EVs from IL-1β-stimulated fibroblast-like synoviocytes have been shown to induce osteoarthritic changes in chondrocytes. RA models have shown that EVs stimulated with inflammatory cytokines are capable of inducing apoptosis resistance in T cells, presenting antigen to T cells, and causing extracellular damage with matrix-degrading enzymes. EVs derived from rheumatoid models have also been shown to induce secretion of COX-2 and stimulate angiogenesis. Additionally, there is evidence that synovium-derived EVs may be promising biomarkers of disease in both OA and RA. The characterization of EVs in the joint space has also opened up the possibility for delivery of small molecules. This article reviews current knowledge on the role of EVs in both RA and OA, and their potential role as therapeutic targets for modulation of these debilitating diseases.

Keywords: Chondrocyte; Extracellular vesicles; Fibroblast-like synoviocyte; IL-1β; MMP-13; MicroRNA; TNF-α.

Fig. 1

TNF-α in the joint fluid stimulates FLS to increase microRNAs miR-155 and miR-146. miR-155 stimulates production of Src homology 2-containing inositol phosphatase-1 (SHIP-1), Fas-associated death domain protein (FADD), and Serine-threonine kinase 1 (Ripk1) to promote inflammation and increase TNF-α production by the FLS. miR-146a downregulates TNF receptor associated factor 6 (TRAF6) and IL-1 receptor associated kinase 1 (IRAK1) to suppress inflammation and decrease TNF-α production. Additionally, these miRNA are found in the joint space of patients with RA and increased in EVs released by dendritic cells in response to inflammation

Fig. 2

Proposed mechanism of EV communication between FLS and chondrocytes in OA. EVs from FLS stimulated with inflammatory cytokines in the synovial fluid are released into the synovial fluid act on chondrocytes to increase MMP-13 and ADAMTS-5. EVs from chondrocytes stimulated with inflammatory cytokines are released into the joint space and increase MMP-13, COX-2, IL-1β, and TNF-α. This positive feedback cycle leads to further breakdown of the articular cartilage ECM. COX-2 cyclooxygenase 2, ECM extracellular matrix, EV extracellular vesicle, miRNA microRNA, MMP matrix metalloproteinase

Fig. 3

a Concentration of EVs in synovial fluid (x axis) versus the average size of EVs (y axis). There was no significant difference in either measurement between EVs from OA patients and EVs from normal patients. b Top row, chondrocytes treated with DAPI and unlabeled EVs; bottom row, chondrocytes treated with DAPI and PKH67-labeled EVs. Left column, only DAPI labeling; middle column, only PKH67 labeling; right column, combination of DAPI and PKH67 labeling. EV extracellular vesicle, OA osteoarthritis