Dynamic synovial fibroblasts are modulated by NBCn1 as a potential target in rheumatoid arthritis

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.

Addition of oh8dG to Cardioplegia Attenuated Myocardial Oxidative Injury through the Inhibition of Sodium Bicarbonate Cotransporter Activity

“…NBC activity is modulated by various cellular stimulants, such as ROS [ 18 ], acidic [ 49 ], hypoxia [ 50 ], and inflammatory cytokines [ 49 ]. Our previous study showed that HTK-induced arrest mediated more acidic intracellular circumstances through the involvement of sodium-potassium-chloride cotransporter Nkcc1 and chloride-bicarbonate exchanger Slc26a6 in the db/db diabetic mouse model’s heart than in wild-type mice during reperfusion [ 38 ].…”

“…Ras signaling is involved in migration in various cellular systems, such as vascular smooth muscle cells, endothelial cells, and several cancers [ 54 , 55 , 56 , 57 ]. In addition, NBCn is known to provide a migratory module in various cell types, such as vascular smooth muscle cells, breast cancers, and synoviocytes [ 49 , 58 , 59 ]. Currently, there is no direct evidence for an association between Ras and NBCn.…”

Solute carrier nutrient transporters in rheumatoid arthritis fibroblast-like synoviocytes

“…SLC, solute carrier; Glu, glutamate; Asp, aspartate; Ala, alanine; Asn, asparagine; Cys, cysteine; His, histidine; Ser, Serine; Zn, zinc; Cd, Cadmium; Mn, Magnesium; T3, Triiodothyronine; T4, Thyroxine; L-DOPA, L-Dopamine; AA, amino acids; BCH, 2-aminobicyclo-(2, 2, 1)-heptane-2-carboxylic acid. (12,42). Upon siRNA knockdown of SLC4A4, RA FLS were found to be more invasive but with unchanged migration compared to control siRNA (12).…”

“…In the context of these transporters playing a known role in migration of other cell types, one group has investigated the role of bicarbonate transporters on RA FLS migrations. Upon testing various genes of the SLC4 family, SLC4A7 (also known as NBCn1) was shown to be significantly increased in RA FLS upon TNF-a expression as compared to OA FLS ( 42 ). As a result, TNF stimulation significantly increased migration.…”

Advancement in understanding the role of ferroptosis in rheumatoid arthritis

“…Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) lead to the proliferation of synovial membrane, inflammatory reactions, extensive angiogenesis, the disintegration of cartilage matrix, and destruction of bones by producing abundant pro-inflammatory cytokines and chemokines ( Bartok and Firestein, 2010 ; Aldridge et al, 2020 ; Bai et al, 2022 ; Ji et al, 2022 ); Figure 1 ). RA-FLS continuously produces many inflammatory factors like IL-6, IL-1β, TNF-α, vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMPs).…”