MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress
Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positivel...
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07193-5 |
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| author | Zhengmeng Yang Nan Hou Wenxiang Cheng Xuan Lu Ming Wang Shanshan Bai Yuejun Lin Yaofeng Wang Sien Lin Peng Zhang Micky D. Tortorella Lu Feng Gang Li |
| author_facet | Zhengmeng Yang Nan Hou Wenxiang Cheng Xuan Lu Ming Wang Shanshan Bai Yuejun Lin Yaofeng Wang Sien Lin Peng Zhang Micky D. Tortorella Lu Feng Gang Li |
| author_sort | Zhengmeng Yang |
| collection | DOAJ |
| description | Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378high) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment. |
| format | Article |
| id | doaj-art-608526ac6dbf44cc8b6a4e8be1747b7c |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-608526ac6dbf44cc8b6a4e8be1747b7c2024-12-22T12:51:06ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151211310.1038/s41419-024-07193-5MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stressZhengmeng Yang0Nan Hou1Wenxiang Cheng2Xuan Lu3Ming Wang4Shanshan Bai5Yuejun Lin6Yaofeng Wang7Sien Lin8Peng Zhang9Micky D. Tortorella10Lu Feng11Gang Li12Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of SciencesStem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalInstitute of Translation and Medical Research and Development Center, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesCentre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of SciencesStem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalCentre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of SciencesStem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalCentre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of SciencesStem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalInstitute of Translation and Medical Research and Development Center, Shenzhen Institute of Advanced Technology, Chinese Academy of SciencesCentre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of SciencesCentre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of SciencesStem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales HospitalAbstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by pain, inflammation, and discomfort in the synovial joints. It is critical to understand the pathological mechanisms of RA progression. MicroRNA-378 (miR-378) is highly expressed in the synovium of RA patients and positively correlated with disease severity, but its function and underlying mechanisms remain poorly understood. In this study, miR-378 transgenic (miR-378high) mice were used to construct the collagen-induced arthritis (CIA) model for exploring the role of miR-378 in RA development. miR-378high CIA mice showed accelerated RA development, as evidenced by exaggerated joint swelling and bone structural deformities. More severe endoplasmic reticulum (ER) stress and the consequent angiogenesis and osteoclastogenesis were also activated in the synovial tissue and calcaneus, respectively, in the miR-378high group, suggesting that ER plays a significant role in miR-378-mediated RA pathogenesis. Upon in vitro RA induction, fibroblast-like synoviocytes (FLSs) isolated from miR-378high mice showed a higher expression level of ER stress markers. The conditioned medium (CM) from RA-FLSs of miR-378high mice stimulated more intensive angiogenesis and osteoclastogenesis. The ER stress-related protein Crebrf was identified as a downstream target of miR-378. Crebrf knockdown diminished the promoting effect of miR-378 on ER stress, as well as its downstream angiogenesis and osteoclastogenesis activities. Tail vein injection of anti-miR-378 lentivirus in an established RA mouse model was shown to ameliorate RA progression. In conclusion, miR-378 amplified RA development by promoting ER stress and downstream angiogenesis and osteoclastogenesis, thus indicating that miR-378 may be a potential therapeutic target for RA treatment.https://doi.org/10.1038/s41419-024-07193-5 |
| spellingShingle | Zhengmeng Yang Nan Hou Wenxiang Cheng Xuan Lu Ming Wang Shanshan Bai Yuejun Lin Yaofeng Wang Sien Lin Peng Zhang Micky D. Tortorella Lu Feng Gang Li MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress Cell Death and Disease |
| title | MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress |
| title_full | MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress |
| title_fullStr | MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress |
| title_full_unstemmed | MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress |
| title_short | MiR-378 exaggerates angiogenesis and bone erosion in collagen-induced arthritis mice by regulating endoplasmic reticulum stress |
| title_sort | mir 378 exaggerates angiogenesis and bone erosion in collagen induced arthritis mice by regulating endoplasmic reticulum stress |
| url | https://doi.org/10.1038/s41419-024-07193-5 |
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