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 ag...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-12-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03781-1 |
| _version_ | 1811190266108837888 |
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| author | Zhuoyan Zai Yayun Xu Xuewen Qian Zihan Li Ziyao Ou Tao Zhang Longfei Wang Yian Ling Xiaoqing Peng Yihao Zhang Feihu Chen |
| author_facet | Zhuoyan Zai Yayun Xu Xuewen Qian Zihan Li Ziyao Ou Tao Zhang Longfei Wang Yian Ling Xiaoqing Peng Yihao Zhang Feihu Chen |
| author_sort | Zhuoyan Zai |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T14:47:21Z |
| format | Article |
| id | doaj.art-9983a6f67e114f20bc14e28d1cb3376b |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-11T14:47:21Z |
| publishDate | 2022-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-9983a6f67e114f20bc14e28d1cb3376b2022-12-22T04:17:35ZengBMCJournal of Translational Medicine1479-58762022-12-0120111410.1186/s12967-022-03781-1Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritisZhuoyan Zai0Yayun Xu1Xuewen Qian2Zihan Li3Ziyao Ou4Tao Zhang5Longfei Wang6Yian Ling7Xiaoqing Peng8Yihao Zhang9Feihu Chen10School of Pharmacy, Anhui Medical UniversitySchool of Public Health, Anhui Medical UniversitySchool of Pharmacy, Anhui Medical UniversitySchool of Pharmacy, Anhui Medical UniversitySchool of Pharmacy, Anhui Medical UniversitySchool of Pharmacy, Anhui Medical UniversitySchool of Pharmacy, Anhui Medical UniversitySchool of Pharmacy, Anhui Medical UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical UniversityDepartment of Toxicology, School of Public Health, Anhui Medical UniversitySchool of Pharmacy, Anhui Medical UniversityAbstract 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.https://doi.org/10.1186/s12967-022-03781-1Rheumatoid arthritisASIC1aCalcium influxMitochondrial stressEstrogen |
| spellingShingle | Zhuoyan Zai Yayun Xu Xuewen Qian Zihan Li Ziyao Ou Tao Zhang Longfei Wang Yian Ling Xiaoqing Peng Yihao Zhang Feihu Chen Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis Journal of Translational Medicine Rheumatoid arthritis ASIC1a Calcium influx Mitochondrial stress Estrogen |
| title | Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis |
| title_full | Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis |
| title_fullStr | Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis |
| title_full_unstemmed | Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis |
| title_short | Estrogen antagonizes ASIC1a-induced chondrocyte mitochondrial stress in rheumatoid arthritis |
| title_sort | estrogen antagonizes asic1a induced chondrocyte mitochondrial stress in rheumatoid arthritis |
| topic | Rheumatoid arthritis ASIC1a Calcium influx Mitochondrial stress Estrogen |
| url | https://doi.org/10.1186/s12967-022-03781-1 |
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