Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis

Abstract

Background Destruction of articular cartilage and bone is the main cause of joint dysfunction in rheumatoid arthritis (RA). Acid-sensing ion channel 1a (ASIC1a) is a key molecule that mediates the destruction of RA articular cartilage. Estrogen has been proven to have a protective effect against articular cartilage damage, however, the underlying mechanisms remain unclear. Methods We treated rat articular chondrocytes with an acidic environment, analyzed the expression levels of mitochondrial stress protein HSP10, ClpP, LONP1 by q-PCR and immunofluorescence staining. Transmission electron microscopy was used to analyze the mitochondrial morphological changes. Laser confocal microscopy was used to analyze the Ca2+, mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) level. Moreover, ASIC1a specific inhibitor Psalmotoxin 1 (Pctx-1) and Ethylene Glycol Tetraacetic Acid (EGTA) were used to observe whether acid stimulation damage mitochondrial function through Ca2+ influx mediated by ASIC1a and whether pretreatment with estrogen could counteract these phenomena. Furthermore, the ovariectomized (OVX) adjuvant arthritis (AA) rat model was treated with estrogen to explore the effect of estrogen on disease progression. Results Our results indicated that HSP10, ClpP, LONP1 protein and mRNA expression and mitochondrial ROS level were elevated in acid-stimulated chondrocytes. Moreover, acid stimulation decreased mitochondrial membrane potential and damaged mitochondrial structure of chondrocytes. Furthermore, ASIC1a specific inhibitor PcTx-1 and EGTA inhibited acid-induced mitochondrial abnormalities. In addition, estrogen could protect acid-stimulated induced mitochondrial stress by regulating the activity of ASIC1a in rat chondrocytes and protects cartilage damage in OVX AA rat. Conclusions Extracellular acidification induces mitochondrial stress by activating ASIC1a, leading to the damage of rat articular chondrocytes. Estrogen antagonizes acidosis-induced joint damage by inhibiting ASIC1a activity. Our study provides new insights into the protective effect and mechanism of action of estrogen in RA.

Circular RNA CircFOXO3 Functions as a Competitive Endogenous RNA for Acid-Sensing Ion Channel Subunit 1 Mediating Oxeiptosis in Nucleus Pulposus

“…Previous studies on ASIC1 and ROS have primarily focused on the proton-gated characteristics of ASIC1, often involving stimulation with acidic external environments. For instance, Zai et al conducted research on rat chondrocytes and found that extracellular acidification leads to an elevation in mitochondrial ROS levels by activating ASIC1 [ 65 ]. In another study, Zhao et al reported that extracellular lactate regulated intercellular ROS levels through ASIC1 and ASIC3 in NP cells [ 47 ].…”

The Genetic Selection of HSPD1 and HSPE1 Reduce Inflammation of Liver and Spleen While Restraining the Growth and Development of Skeletal Muscle in Wuzhishan Pigs

“…Indeed, it was reported that the HSPD1-derived altered peptide ligand reduced the pro-inflammatory cytokines in rheumatoid arthritis disease and also in COVID-19 patients [ 48 ]; in addition, HSPE1 inhibited lipopolysaccharide-induced inflammation by interacting with HSPD1 [ 49 ]. However, HSPD1 was also found to be upregulated and to act as an initiator of oxidative stress and neuroinflammation in diabetes [ 15 ], and HSPE1 stimulated mitochondrial stress and damaged the mitochondrial structure of chondrocytes [ 50 ]. In this study, although both HSPD1 and HSPE1 were significantly more highly expressed in the liver and spleen tissues of WZS pigs compared with LW pigs, the expression of most JAK3-STAT pathway-related genes ( JAK3 , STAT1 , STAT2 , STAT4 , and TICAM1 ) was significantly lower in liver tissue.…”

Sequencing and bioinformatics analysis of miRNA from rat endplate chondrogenic exosomes

“…One-week-old Sprague Dawley (SD) rats were used. Due to the protective effect of estrogen on chondrocytes ( 13 ), these rats were selected for use in the present study. They were donated by Nanjing Qinglongshan Zoo (Nanjing, China) and were maintained under standard specific pathogen-free conditions.…”