Abstract
BackgroundLong non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was found to be elevated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs). However, whether HAND2-AS1 functions as an exosomal lncRNA related to mesenchymal stem cells (MSCs) in RA progression is unknown.MethodsThe expression of HAND2-AS1, microRNA (miR)-143-3p, and tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) was detected using quantitative real-time polymerase chain reaction and Western blot. Cell proliferation, apoptosis, migration, and invasion were detected using cell counting kit-8, flow cytometry, and wound healing and transwell assays. The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL)-6 were analyzed using enzyme-linked immunosorbent assay. The level of phosphorylated-p65 was examined by Western blot. The binding interaction between miR-143-3p and HAND2-AS1 or TNFAIP3 was confirmed by the dual-luciferase reporter and RIP assays. Exosomes were isolated by ultracentrifugation and qualified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot.ResultsHAND2-AS1 was lowly expressed in RA synovial tissues, and HAND2-AS1 re-expression suppressed the proliferation, motility, and inflammation and triggered the apoptosis in RA-FLSs via the inactivation of NF-κB pathway. Mechanistically, HAND2-AS1 directly sponged miR-143-3p and positively regulated TNFAIP3 expression, the target of miR-143-3p. Moreover, the effects of HAND2-AS1 on RA-FLSs were partially attenuated by miR-143-3p upregulation or TNFAIP3 knockdown. HAND2-AS1 could be packaged into hMSC-derived exosomes and absorbed by RA-FLSs, and human MSC-derived exosomal HAND2-AS1 also repressed above malignant biological behavior of RA-FLSs.ConclusionMSC-derived exosomes participated in the intercellular transfer of HAND2-AS1 and suppressed the activation of RA-FLSs via miR-143-3p/TNFAIP3/NF-κB pathway, which provided a novel insight into the pathogenesis and treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a common systemic and chronic autoimmune disease, highlighted by hyperplasia, hypertrophy, and functional disability of joint structure, leading to incredibly high mortality and morbidity [1, 2]
mesenchymal stem cells (MSCs)-derived exosomes participated in the intercellular transfer of HAND2-AS1 and suppressed the activation of rheumatoid arthritis (RA)-FLSs via miR-143-3p/tumor necrosis factor alpha-inducible protein 3 (TNFAIP3)/NF-κB pathway, which provided a novel insight into the pathogenesis and treatment of RA
HAND2-AS1 served as a sponge for miR-143-3p and positively regulated TNFAIP3 expression, which was a target of miR-143-3p
Summary
Rheumatoid arthritis (RA) is a common systemic and chronic autoimmune disease, highlighted by hyperplasia, hypertrophy, and functional disability of joint structure, leading to incredibly high mortality and morbidity [1, 2]. Growing evidence has indicated that RA fibroblast-like synoviocytes (RA-FLSs) play key roles in the regulation of inflammatory response and joint destruction [3]. Long non-coding RNAs (lncRNAs) are RNA transcripts longer than ∼ 200 nucleotides in length, which can modulate gene expression by a wide diversity of mechanisms [5]. LncRNA heart and neural crest derivatives expressed 2antisense RNA 1 (HAND2-AS1) is a well-recognized tumor suppressor in different types of cancer [11,12,13]. Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (HAND2-AS1) was found to be elevated in rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLSs). Whether HAND2-AS1 functions as an exosomal lncRNA related to mesenchymal stem cells (MSCs) in RA progression is unknown
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