Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged Cartilage
Abstract Susceptibility to cartilage degeneration increases in an age‐dependent manner and older cartilage exhibits increased catabolic factor expression leading to osteoarthritis (OA). While inhibition of cellular senescence can prevent age‐related diseases, the understanding of the regulators gove...
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| Format: | Article |
| Language: | English |
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404311 |
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| author | Jiho Nam Hyunmin Woo Jihye Yang Seok Jung Kim Kwang Pyo Lee Ji Hoon Yu Tae Joo Park Seong‐il Eyun Siyoung Yang |
| author_facet | Jiho Nam Hyunmin Woo Jihye Yang Seok Jung Kim Kwang Pyo Lee Ji Hoon Yu Tae Joo Park Seong‐il Eyun Siyoung Yang |
| author_sort | Jiho Nam |
| collection | DOAJ |
| description | Abstract Susceptibility to cartilage degeneration increases in an age‐dependent manner and older cartilage exhibits increased catabolic factor expression leading to osteoarthritis (OA). While inhibition of cellular senescence can prevent age‐related diseases, the understanding of the regulators governing cartilage senescence and the potential for senolytic intervention remains limited. Here, in vitro and in vivo results are reported, demonstrating for the first time that the transcriptional regulator, ZMIZ1, is upregulated in aged and OA cartilage, and that it acts through GATA4 to accelerate chondrocyte senescence and trigger cartilage deterioration. Furthermore, it is shown that K‐7174 interferes with the ZMIZ1‐GATA4 interaction and effectively hampers cartilage senescence and OA. It is proposed that inhibition of the ZMIZ1‐GATA4 axis could be a valuable strategy for eliminating senescent chondrocytes and impeding OA development and that the relevant inhibitor, K‐7174, could potentially be developed as a senolytic drug for managing cartilage senescence and age‐related degeneration. |
| format | Article |
| id | doaj-art-d60b4edc804644878d4ed4fe53c67bc6 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-d60b4edc804644878d4ed4fe53c67bc62025-08-20T03:14:12ZengWileyAdvanced Science2198-38442025-04-011216n/an/a10.1002/advs.202404311Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged CartilageJiho Nam0Hyunmin Woo1Jihye Yang2Seok Jung Kim3Kwang Pyo Lee4Ji Hoon Yu5Tae Joo Park6Seong‐il Eyun7Siyoung Yang8Department of Biological Science Sungkyunkwan University Suwon 16419 Republic of KoreaDepartment of Life Science Chung‐Ang University Seoul 06974 Republic of KoreaDepartment of Life Science Chung‐Ang University Seoul 06974 Republic of KoreaDepartment of Orthopedic Surgery Uijeongbu St. Mary's Hospital The Catholic University of Korea College of Medicine Uijeongbu 11765 Republic of KoreaAging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon 34141 Republic of KoreaNew Drug Development Center Daegu‐Gyeongbuk Medical Innovation Foundation (K‐MEDI hub) Daegu 41061 Republic of KoreaDepartment of Biological Sciences Ulsan National Institute of Science and Technology (UNIST) Ulsan 44919 Republic of KoreaDepartment of Life Science Chung‐Ang University Seoul 06974 Republic of KoreaDepartment of Biological Science Sungkyunkwan University Suwon 16419 Republic of KoreaAbstract Susceptibility to cartilage degeneration increases in an age‐dependent manner and older cartilage exhibits increased catabolic factor expression leading to osteoarthritis (OA). While inhibition of cellular senescence can prevent age‐related diseases, the understanding of the regulators governing cartilage senescence and the potential for senolytic intervention remains limited. Here, in vitro and in vivo results are reported, demonstrating for the first time that the transcriptional regulator, ZMIZ1, is upregulated in aged and OA cartilage, and that it acts through GATA4 to accelerate chondrocyte senescence and trigger cartilage deterioration. Furthermore, it is shown that K‐7174 interferes with the ZMIZ1‐GATA4 interaction and effectively hampers cartilage senescence and OA. It is proposed that inhibition of the ZMIZ1‐GATA4 axis could be a valuable strategy for eliminating senescent chondrocytes and impeding OA development and that the relevant inhibitor, K‐7174, could potentially be developed as a senolytic drug for managing cartilage senescence and age‐related degeneration.https://doi.org/10.1002/advs.202404311cartilage restorationosteoarthritissenescenceZMIZ1‐GATA4 axis |
| spellingShingle | Jiho Nam Hyunmin Woo Jihye Yang Seok Jung Kim Kwang Pyo Lee Ji Hoon Yu Tae Joo Park Seong‐il Eyun Siyoung Yang Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged Cartilage Advanced Science cartilage restoration osteoarthritis senescence ZMIZ1‐GATA4 axis |
| title | Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged Cartilage |
| title_full | Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged Cartilage |
| title_fullStr | Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged Cartilage |
| title_full_unstemmed | Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged Cartilage |
| title_short | Blockade of ZMIZ1‐GATA4 Axis Regulation Restores Youthfulness to Aged Cartilage |
| title_sort | blockade of zmiz1 gata4 axis regulation restores youthfulness to aged cartilage |
| topic | cartilage restoration osteoarthritis senescence ZMIZ1‐GATA4 axis |
| url | https://doi.org/10.1002/advs.202404311 |
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