Mechanism of Nrf2/miR338-3p/TRAP-1 pathway involved in hyperactivation of synovial fibroblasts in patients with osteoarthritis

by Selleckchem | Jan 01 2024

Our previous study has confirmed that miR338-3p/TRAP-1 axis was involved in regulation of hyperactivation in human synovial fibroblasts (HFLS) of patients with osteoarthritis (OA). Here, we aim to further investigate the underlying causes of the abnormal activation miR338-3p/TRAP-1 at the molecular level. Our results showed that the decrease of NF-E2-related factor 2(Nrf2) was the direct cause of downregulation of miR338-3p and upregulation of TRAP-1 protein expression in HFLS of OA patients. Furthermore, we also found that the phosphorylation and nuclear entry of Nrf2 protein were significantly reduced in HFLS of OA patients than that of normal individuals, and both of them were positively correlated with miR338-3p levels. Bioinformatics analysis, luciferase assay, and CHIP experiment together indicated that Nrf2 could positively regulate the transcription of miR338-3p by binding to the Transcription Factor Binding Sites (TFBS) on its promoter. It was confirmed by in vitro assays that oltipraz (agonists of Nrf2) treatment effectively inhibited the hyperactivation of HFLS induced by TGF-β1, and the effects of oltipraz could be reversed by the exogenous TRAP-1. In short, our research has revealed for the first time that Nrf2/miR338-3p/TRAP-1 pathway was involved in hyperactivation of HFLS in OA patients, Nrf2 has the potential to be used as therapy and new drug target of OA.

Comments:

That's an intriguing study! It seems like you've discovered a significant pathway involved in the hyperactivation of human synovial fibroblasts (HFLS) in patients with osteoarthritis (OA). The involvement of the miR338-3p/TRAP-1 axis and its regulation by NF-E2-related factor 2 (Nrf2) sheds light on potential therapeutic interventions for OA.

Your findings suggest that the decrease in Nrf2 leads to the downregulation of miR338-3p, subsequently upregulating TRAP-1 protein expression in HFLS of OA patients. Moreover, the reduced phosphorylation and nuclear entry of Nrf2 in these patients, along with their correlation with miR338-3p levels, strengthen the connection between Nrf2 and miR338-3p/TRAP-1 axis in OA pathogenesis.

The identification of Nrf2 as a positive regulator of miR338-3p transcription through binding to its promoter via Transcription Factor Binding Sites (TFBS) adds depth to understanding the molecular mechanisms involved. The use of oltipraz, an Nrf2 agonist, shows promise in inhibiting the hyperactivation induced by TGF-β1 in HFLS, underscoring Nrf2's potential as a therapeutic target for OA treatment.

The ability to reverse the effects of oltipraz with exogenous TRAP-1 further supports the interconnectedness of these molecular players in OA pathology. This comprehensive understanding of the Nrf2/miR338-3p/TRAP-1 pathway opens avenues for targeted therapies and potential new drug targets for OA.

Your research presents exciting possibilities for therapeutic interventions and offers a fresh perspective on the molecular intricacies underlying OA pathology. The potential use of Nrf2 as a therapeutic agent and a new drug target could have significant implications for future treatments in managing OA.