Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway
Osteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release of proi...
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| Format: | Article |
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MDPI AG
2021-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/8/3807 |
| _version_ | 1797538589864624128 |
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| author | Dandan Guo Liming He Yaoxin Gao Chenxu Jin Haizhen Lin Li Zhang Liting Wang Ying Zhou Jie Yao Yixin Duan Renzheng Yang Wenwei Qiu Wenzheng Jiang |
| author_facet | Dandan Guo Liming He Yaoxin Gao Chenxu Jin Haizhen Lin Li Zhang Liting Wang Ying Zhou Jie Yao Yixin Duan Renzheng Yang Wenwei Qiu Wenzheng Jiang |
| author_sort | Dandan Guo |
| collection | DOAJ |
| description | Osteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release of proinflammatory cytokines in acute liver failure, but they have not been studied in the progression of OA. In our study, we screened our small synthetic library of OCA derivatives and found T-2054 had anti-inflammatory properties. Meanwhile, the proliferation of RAW 264.7 cells and ATDC5 cells were not affected by T-2054. T-2054 treatment significantly relieved the release of NO, as well as mRNA and protein expression levels of inflammatory cytokines (IL-6, IL-8 and TNF-α) in LPS-induced RAW 264.7 cells. Moreover, T-2054 promoted extracellular matrix (ECM) synthesis in TNF-α-treated ATDC5 chondrocytes. Moreover, T-2054 could relieve the infiltration of inflammatory cells and degeneration of the cartilage matrix and decrease the levels of serum IL-6, IL-8 and TNF-α in DMM-induced C57BL/6 mice models. At the same time, T-2054 showed no obvious toxicity to mice. Mechanistically, T-2054 decreased the extent of p-p65 expression in LPS-induced RAW 264.7 cells and TNF-α-treated ATDC5 chondrocytes. In summary, we showed for the first time that T-2054 effectively reduced the release of inflammatory mediators, as well as promoted extracellular matrix (ECM) synthesis via the NF-κB-signaling pathway. Our findings support the potential use of T-2054 as an effective therapeutic agent for the treatment of OA. |
| first_indexed | 2024-03-10T12:33:35Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T12:33:35Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2090379ce627438786957edd6a25db792023-11-21T14:27:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-04-01228380710.3390/ijms22083807Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling PathwayDandan Guo0Liming He1Yaoxin Gao2Chenxu Jin3Haizhen Lin4Li Zhang5Liting Wang6Ying Zhou7Jie Yao8Yixin Duan9Renzheng Yang10Wenwei Qiu11Wenzheng Jiang12Department of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaShanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, ChinaDepartment of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, ChinaOsteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release of proinflammatory cytokines in acute liver failure, but they have not been studied in the progression of OA. In our study, we screened our small synthetic library of OCA derivatives and found T-2054 had anti-inflammatory properties. Meanwhile, the proliferation of RAW 264.7 cells and ATDC5 cells were not affected by T-2054. T-2054 treatment significantly relieved the release of NO, as well as mRNA and protein expression levels of inflammatory cytokines (IL-6, IL-8 and TNF-α) in LPS-induced RAW 264.7 cells. Moreover, T-2054 promoted extracellular matrix (ECM) synthesis in TNF-α-treated ATDC5 chondrocytes. Moreover, T-2054 could relieve the infiltration of inflammatory cells and degeneration of the cartilage matrix and decrease the levels of serum IL-6, IL-8 and TNF-α in DMM-induced C57BL/6 mice models. At the same time, T-2054 showed no obvious toxicity to mice. Mechanistically, T-2054 decreased the extent of p-p65 expression in LPS-induced RAW 264.7 cells and TNF-α-treated ATDC5 chondrocytes. In summary, we showed for the first time that T-2054 effectively reduced the release of inflammatory mediators, as well as promoted extracellular matrix (ECM) synthesis via the NF-κB-signaling pathway. Our findings support the potential use of T-2054 as an effective therapeutic agent for the treatment of OA.https://www.mdpi.com/1422-0067/22/8/3807T-2054osteoarthritisRAW 264.7 cell lineATDC5 chondrocytesNF-κB-signaling |
| spellingShingle | Dandan Guo Liming He Yaoxin Gao Chenxu Jin Haizhen Lin Li Zhang Liting Wang Ying Zhou Jie Yao Yixin Duan Renzheng Yang Wenwei Qiu Wenzheng Jiang Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway International Journal of Molecular Sciences T-2054 osteoarthritis RAW 264.7 cell line ATDC5 chondrocytes NF-κB-signaling |
| title | Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway |
| title_full | Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway |
| title_fullStr | Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway |
| title_full_unstemmed | Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway |
| title_short | Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway |
| title_sort | obeticholic acid derivative t 2054 suppresses osteoarthritis via inhibiting nf κb signaling pathway |
| topic | T-2054 osteoarthritis RAW 264.7 cell line ATDC5 chondrocytes NF-κB-signaling |
| url | https://www.mdpi.com/1422-0067/22/8/3807 |
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