Influences of the lncRNA TUG1-miRNA-34a-5p network on fibroblast-like synoviocytes (FLSs) dysfunction in rheumatoid arthritis through targeting the lactate dehydrogenase A (LDHA)

Abstract

Background: Rheumatoid arthritis (RA) is a systemic and chronic inflammatory disease. The cellular glucose metabolism of fibroblast-like synoviocytes (FLSs) of RA has been revealed to be essential to the pathogenesis and development of RA. To date, the precise roles and molecular mechanisms of long noncoding RNA TUG1 in RA have not been elucidated.

Methods: TUG1 and miR-34a-5p were detected by qRT-PCR. Interactions between lncRNA-miRNA and miRNA-mRNA were validated by RNA pull-down assay and luciferase assay. The glucose metabolism was evaluated by glucose uptake and extracellular acidification rate (ECAR). Cell viability was determined by MTT assay and Annexin V assay.

Results: TUG1 expression was significantly upregulated in synovial fibroblast-like synoviocytes (FLSs) compared with normal FLSs. Functional assays uncovered that silence of TUG1 suppressed FLSs-RA invasion, migration, glucose metabolism, and increased apoptosis. Bioinformatics analysis indicated that TUG1 interacted with miR-34a-5p. RNA pull-down assay and luciferase assay validated that TUG1 sponged miR-34a-5p in FLSs-RA. Overexpression of miR-34a-5p effectively inhibited glucose metabolism of FLSs-RA. Furthermore, the glucose metabolism of FLSs-RA was significantly elevated compared with normal FLSs. The glucose metabolism enzyme, LDHA, was directly targeted by miR-34a-5p in FLSs. Rescue experiments validated that the miR-34a-5p-inhibited glucose metabolism of FLSs-RA was through targeting LDHA. Finally, we showed restoration of miR-34a-5p in TUG1-overexpressing FLSs-RA successfully overcame the TUG1-promoted glucose metabolism and apoptosis resistance via targeting LDHA.

Conclusion: The present study uncovered critical roles and molecular mechanisms underlying the TUG1-mediated glucose metabolism and apoptosis of FLSs-RA through modulating the miR-34a-5p-LDHA pathway in fibroblast-like synoviocytes of rheumatoid arthritis.

Keywords: TUG1; fibroblast-like synoviocytes; glycolysis; miR-34a-5p; rheumatoid arthritis.