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Abstract
Rheumatoid arthritis (RA), a chronic systemic inflammatory disease, is a primary cause of disability worldwide. The involvement of fibroblast-like synoviocytes (FLSs) in the regulation of the pathogenesis of RA has been highlighted. Mesenchymal stem cells (MSCs) are important candidates for cell-based treatment in many inflammatory autoimmune diseases. Herein, we identify whether MSC-derived exosomes loaded with microRNA-320a (miR-320a) regulate RA-FLSs. Synovial tissues from 22 patients with RA and 9 patients with osteoarthritis were collected. RA-FLSs were obtained from patients with RA, and their functions were evaluated by determining levels of interleukin-1β (IL-1β), IL-6, and IL-8 and by transwell migration and invasion assays. Dual luciferase reporter gene assays were employed to identify interaction between miR-320a and CXC chemokine ligand 9 (CXCL9). A co-culture system of MSC-derived exosomes and RA-FLSs were performed. The collagen-induced arthritis (CIA) mouse models with arthritis and bone damage were developed. Our results revealed the existence of reciprocal expression of miR-320a and CXCL9 in the synovial tissues obtained from patients with RA. CXCL9 knockdown or miR-320a upregulation suppressed the activation, migration, and invasion of RA-FLSs. CXCL9 was confirmed to be a target of miR-320a, and CXCL9 overexpression restored RA-FLS function in the presence of miR-320a. MSC-derived exosomes containing miR-320a mimic significantly suppressed RA-FLS activation, migration, and invasion in vitro and attenuated arthritis and bone damage in mice with CIA in vivo. Our study uncovers that MSC-derived exosomes participate in the intercellular transfer of miR-320a and subsequently inhibit the progression of RA. These results provide a novel potential therapeutic approach for RA treatment by increasing miR-320a in exosomes.
Highlights
MATERIALS AND METHODSAs a systemic and chronic autoimmune disease, rheumatoid arthritis (RA) influences the lining of the synovial joints often leading to disability, premature death, and social and economic burdens of human beings (Guo et al, 2018)
The results revealed that CD27, CD79A, CXCL10, and CXC chemokine ligand 9 (CXCL9) were at the center of the entire network (Figure 1B)
The results of hematoxylin and eosin (H&E) staining revealed that in comparison with that of patients with OA, the inflammatory cell infiltration was observed in the synovial tissues of patients with RA, and the angiogenesis was significantly increased (Figure 1C)
Summary
As a systemic and chronic autoimmune disease, rheumatoid arthritis (RA) influences the lining of the synovial joints often leading to disability, premature death, and social and economic burdens of human beings (Guo et al, 2018). Fibroblast-like synoviocytes (FLSs) have been widely documented to be effectors of cartilage destruction in RA and play a crucial role in initiating and maintaining the inflammatory and destructive processes in the rheumatoid joint (Bottini and Firestein, 2013; Bustamante et al, 2017). It has been known that human MSCs have capacities of producing a mass of exosomes (Yeo et al, 2013). MSC-derived exosomes have been shown to suppress T and B lymphocytes to exert therapeutic effects on inflammatory arthritis (Cosenza et al, 2018)
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