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Generation of Induced-pluripotent Stem Cells Using Fibroblast-like Synoviocytes Isolated from Joints of Rheumatoid Arthritis Patients
Published on: October 16, 2016
Dynamic synovial fibroblasts are modulated by NBCn1 as a potential target in rheumatoid arthritis
Minjeong Ji1,2, Hee Jung Ryu3, Hyeon-Man Baek4,5
1Department of Physiology, College of Medicine, Gachon University, Lee Gil Ya Cancer and Diabetes Institute, 155 Getbeolro, Yeonsu-gu, Incheon, South Korea.
Abstract:
Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive fibroblast-like synoviocytes (FLSs) and pannus formation. Various therapeutic strategies have been developed against inflammatory cytokines in RA in recent decades. Based on the migratory features of FLSs, we examined whether modulation of the migratory module attenuates RA severity. In this study, inflamed synovial fluid-stimulated FLSs exhibited enhanced migration and migratory apparatus expression, and sodium bicarbonate cotransporter n1 (NBCn1) was identified in primary cultured RA-FLSs for the first time. The NBC inhibitor S0859 attenuated the migration of FLSs induced with synovial fluid from patients with RA or with TNF-α stimulation. Inhibition of NBCs with S0859 in a collagen-induced arthritis (CIA) mouse model reduced joint swelling and destruction without blood, hepatic, or renal toxicity. Primary FLSs isolated from the CIA-induced mouse model also showed reduced migration in the presence of S0859. Our results suggest that inflammatory mediators in synovial fluid, including TNF-α, recruit NBCn1 to the plasma membrane of FLSs to provide dynamic properties and that modulation of NBCn1 could be developed into a therapeutic strategy for RA.
Insights
Modulating sodium bicarbonate cotransporter n1 (NBCn1) in fibroblast-like synoviocytes (FLSs) reduced rheumatoid arthritis (RA) severity. Targeting NBCn1 offers a potential new therapeutic strategy for RA patients.
Area of Science:
- Immunology
- Cell Biology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) is an autoimmune disease driven by aggressive fibroblast-like synoviocytes (FLSs) and pannus formation.
- Current RA therapies target inflammatory cytokines, but FLS migration is a key factor in disease progression.
- Investigating FLS migratory mechanisms offers potential for novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of FLS migration in RA pathogenesis.
- To identify key molecular targets within the FLS migratory apparatus.
- To evaluate the therapeutic potential of modulating FLS migration in an RA model.
Main Methods:
- Primary RA-FLSs were cultured and stimulated with inflamed synovial fluid or TNF-α.
- Sodium bicarbonate cotransporter n1 (NBCn1) expression and function were assessed.
- FLS migration was inhibited using the NBC inhibitor S0859.
- A collagen-induced arthritis (CIA) mouse model was used to evaluate therapeutic efficacy and toxicity.
Main Results:
- Inflamed synovial fluid-stimulated RA-FLSs showed enhanced migration and increased expression of migratory apparatus components.
- NBCn1 was identified in primary cultured RA-FLSs for the first time.
- S0859 significantly attenuated RA-FLS migration induced by synovial fluid or TNF-α.
- Inhibition of NBCs with S0859 in the CIA mouse model reduced joint swelling and destruction without significant toxicity.
Conclusions:
- Inflammatory mediators recruit NBCn1 to the FLS plasma membrane, contributing to their migratory properties.
- Modulation of NBCn1 represents a promising therapeutic strategy for rheumatoid arthritis.
- Targeting NBCn1 could offer a novel approach to managing RA by inhibiting FLS migration and subsequent joint damage.
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