Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation
Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflam...
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Elsevier
2025-08-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525004356 |
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| author | Peitao Xu Guiwen Ye Xiaojun Xu Zhidong Liu Wenhui Yu Guan Zheng Zepeng Su Jiajie Lin Yunshu Che Yipeng Zeng Zhikun Li Pei Feng Qian Cao Zhongyu Xie Yanfeng Wu Huiyong Shen Jinteng Li |
| author_facet | Peitao Xu Guiwen Ye Xiaojun Xu Zhidong Liu Wenhui Yu Guan Zheng Zepeng Su Jiajie Lin Yunshu Che Yipeng Zeng Zhikun Li Pei Feng Qian Cao Zhongyu Xie Yanfeng Wu Huiyong Shen Jinteng Li |
| author_sort | Peitao Xu |
| collection | DOAJ |
| description | Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis. |
| format | Article |
| id | doaj-art-33ecd5a29a024ed0818137617f2ff024 |
| institution | Kabale University |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-33ecd5a29a024ed0818137617f2ff0242025-08-20T05:06:38ZengElsevierActa Pharmaceutica Sinica B2211-38352025-08-011584064407710.1016/j.apsb.2025.06.015Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulationPeitao Xu0Guiwen Ye1Xiaojun Xu2Zhidong Liu3Wenhui Yu4Guan Zheng5Zepeng Su6Jiajie Lin7Yunshu Che8Yipeng Zeng9Zhikun Li10Pei Feng11Qian Cao12Zhongyu Xie13Yanfeng Wu14Huiyong Shen15Jinteng Li16Department of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaCenter for Biotherapy, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaCenter for Biotherapy, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaDepartment of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, ChinaCenter for Biotherapy, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, China; Corresponding authors.Department of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, China; Corresponding authors.Department of Orthopedics, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen 518003, China; Corresponding authors.Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.http://www.sciencedirect.com/science/article/pii/S2211383525004356ArthritisWACCartilage degradationChondrocyte secretionHistone modificationDoxercalciferol |
| spellingShingle | Peitao Xu Guiwen Ye Xiaojun Xu Zhidong Liu Wenhui Yu Guan Zheng Zepeng Su Jiajie Lin Yunshu Che Yipeng Zeng Zhikun Li Pei Feng Qian Cao Zhongyu Xie Yanfeng Wu Huiyong Shen Jinteng Li Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation Acta Pharmaceutica Sinica B Arthritis WAC Cartilage degradation Chondrocyte secretion Histone modification Doxercalciferol |
| title | Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation |
| title_full | Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation |
| title_fullStr | Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation |
| title_full_unstemmed | Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation |
| title_short | Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via H2BK120ub1 and H3K27me3 coregulation |
| title_sort | inhibition of wac alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradation via h2bk120ub1 and h3k27me3 coregulation |
| topic | Arthritis WAC Cartilage degradation Chondrocyte secretion Histone modification Doxercalciferol |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525004356 |
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