MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2
Abstract Osteoarthritis (OA), the most prevalent degenerative joint disease, is marked by cartilage degradation and pathological alterations in surrounding tissues. Currently, no effective disease-modifying treatments exist. This study aimed to elucidate the critical roles of Myb-like, SWIRM, and MP...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-024-00368-y |
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| _version_ | 1841559809760952320 |
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| author | Kang Wei Chuankun Zhou Zixing Shu Xingru Shang Yi Zou Wei Zhou Huanhuan Xu Yulin Liang Tian Ma Xuying Sun Jun Xiao |
| author_facet | Kang Wei Chuankun Zhou Zixing Shu Xingru Shang Yi Zou Wei Zhou Huanhuan Xu Yulin Liang Tian Ma Xuying Sun Jun Xiao |
| author_sort | Kang Wei |
| collection | DOAJ |
| description | Abstract Osteoarthritis (OA), the most prevalent degenerative joint disease, is marked by cartilage degradation and pathological alterations in surrounding tissues. Currently, no effective disease-modifying treatments exist. This study aimed to elucidate the critical roles of Myb-like, SWIRM, and MPN domains 1 (MYSM1) and its downstream effector, Receptor-interacting protein kinase 2 (RIPK2), in OA pathogenesis and the underlying mechanisms. Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models. Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice, whereas MYSM1 overexpression mitigated it. Mechanistically, MYSM1 inhibited the NF-κB and MAPK signaling pathways. Conversely, downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways. The Ripk2 S176D mutation accelerated OA pathogenesis, while Ripk2 silencing or Ripk2 S176A mutation deactivated NF-κB and MAPK pathways, counteracting the role of MYSM1. MYSM1 deubiquitinates and dephosphorylates RIPK2S176 by recruiting protein phosphatase 2 A (PP2A). These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA. |
| format | Article |
| id | doaj-art-5f627fcc708b46139144e4fb23eb5c45 |
| institution | Kabale University |
| issn | 2095-6231 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj-art-5f627fcc708b46139144e4fb23eb5c452025-01-05T12:11:09ZengNature Publishing GroupBone Research2095-62312025-01-0113111310.1038/s41413-024-00368-yMYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2Kang Wei0Chuankun Zhou1Zixing Shu2Xingru Shang3Yi Zou4Wei Zhou5Huanhuan Xu6Yulin Liang7Tian Ma8Xuying Sun9Jun Xiao10Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hepatobiliary Diseases, Transplant Center, Hubei Key Laboratory of Medical Technology on Transplantation, Zhongnan Hospital of Wuhan UniversityDepartment of Obstetrics and Gynecology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Osteoarthritis (OA), the most prevalent degenerative joint disease, is marked by cartilage degradation and pathological alterations in surrounding tissues. Currently, no effective disease-modifying treatments exist. This study aimed to elucidate the critical roles of Myb-like, SWIRM, and MPN domains 1 (MYSM1) and its downstream effector, Receptor-interacting protein kinase 2 (RIPK2), in OA pathogenesis and the underlying mechanisms. Our findings revealed reduced MYSM1 levels in the cartilage of OA patients and mouse models. Genetic or adenovirus-induced MYSM1 knockout exacerbated OA progression in mice, whereas MYSM1 overexpression mitigated it. Mechanistically, MYSM1 inhibited the NF-κB and MAPK signaling pathways. Conversely, downstream RIPK2 significantly increased OA-like phenotypes and activated the NF-κB and MAPK pathways. The Ripk2 S176D mutation accelerated OA pathogenesis, while Ripk2 silencing or Ripk2 S176A mutation deactivated NF-κB and MAPK pathways, counteracting the role of MYSM1. MYSM1 deubiquitinates and dephosphorylates RIPK2S176 by recruiting protein phosphatase 2 A (PP2A). These results suggest that targeting MYSM1 or downstream RIPK2 offers promising therapeutic potential for OA.https://doi.org/10.1038/s41413-024-00368-y |
| spellingShingle | Kang Wei Chuankun Zhou Zixing Shu Xingru Shang Yi Zou Wei Zhou Huanhuan Xu Yulin Liang Tian Ma Xuying Sun Jun Xiao MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2 Bone Research |
| title | MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2 |
| title_full | MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2 |
| title_fullStr | MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2 |
| title_full_unstemmed | MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2 |
| title_short | MYSM1 attenuates osteoarthritis by recruiting PP2A to deubiquitinate and dephosphorylate RIPK2 |
| title_sort | mysm1 attenuates osteoarthritis by recruiting pp2a to deubiquitinate and dephosphorylate ripk2 |
| url | https://doi.org/10.1038/s41413-024-00368-y |
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