The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity
Abstract Background Hypoxia can affect the occurrence and development of inflammation in humans, but its effects on the disease progression of osteoarthritis (OA) remain unclear. Synovial macrophages play an essential role in the progression of arthritis. Specifically, the activation of the NOD‐like...
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Wiley
2025-01-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70118 |
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| author | Ao Duan Zemeng Ma Xiaolong Shao Zhencheng Xiong Chaoyi Zhang Wenzheng Liu Guanglin Wang Shouye Hu Wei Lin |
| author_facet | Ao Duan Zemeng Ma Xiaolong Shao Zhencheng Xiong Chaoyi Zhang Wenzheng Liu Guanglin Wang Shouye Hu Wei Lin |
| author_sort | Ao Duan |
| collection | DOAJ |
| description | Abstract Background Hypoxia can affect the occurrence and development of inflammation in humans, but its effects on the disease progression of osteoarthritis (OA) remain unclear. Synovial macrophages play an essential role in the progression of arthritis. Specifically, the activation of the NOD‐like receptor family pyrin domain containing 3 (NLRP3) in macrophages induces the secretion of a series of inflammatory factors, accelerating the progression of OA. Methods The effects of CBR‐470‐1 were assessed in a mouse model of OA induced by destabilization of the medial meniscus (DMM) by micro‐computed tomography imaging, Safranin‐O and Fast Green staining, immunofluorescence staining and enzyme‐linked immunosorbent assay. Western Blot analysis was used to explore the underlying mechanism of these experimental results. Additionally, a co‐culture system of THP‐1 and chondrocytes was established to investigate the impact of CBR‐470‐1 on chondrocyte proliferation, apoptosis, migration and the regulation of chondrocyte‐related proteins within the system. Results In hypoxic conditions, CBR‐470‐1 significantly inhibited the progression of OA in the DMM‐induced OA mouse model, but that effect disappeared in the DMM‐induced OA phosphoglycerate kinase 1 (PGK1)fl/flLyz2‐Cre mouse model. Not only that, CBR‐470‐1 can also improve the proliferation and migration of chondrocytes, reduce the apoptosis rate of chondrocytes, and regulate the expression of chondrocyte‐related proteins in the co‐culture system of THP‐1 and chondrocytes. Conclusions This study conducted a series of in vitro and in vivo experiments, revealing that hypoxia plays a pro‐inflammatory role by increasing PGK1 activity and reducing the binding of the deubiquitinating enzyme ubiquitin‐specific peptidase 14 to NLRP3, thereby reducing the ubiquitination level of NLRP3. CBR‐470‐1, a specific inhibitor of PGK1, can reduce PGK1 activity to reverse the role of hypoxia in the progression of OA. These findings lay a foundation for the development of OA treatment in a hypoxic environment. Key points Hypoxia plays a pro‐inflammatory role by increasing PGK1 activity and thereby decreasing the ubiquitination level of NLRP3. Hypoxia plays a pro‐inflammatory role by increasing PGK1 activity, reducing the binding of the deubiquitinating enzyme USP14 to NLRP3, and reducing the ubiquitination level of NLRP3. CBR‐470‐1 reverses the role of hypoxia in the progression of osteoarthritis. |
| format | Article |
| id | doaj-art-df8a6d6529b543b7a151a2cf7808ef24 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-df8a6d6529b543b7a151a2cf7808ef242025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70118The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activityAo Duan0Zemeng Ma1Xiaolong Shao2Zhencheng Xiong3Chaoyi Zhang4Wenzheng Liu5Guanglin Wang6Shouye Hu7Wei Lin8Department of Orthopedics SurgeryTrauma Medical CentreWest China Hospital, Sichuan UniversityChengduChinaDepartment of Joint SurgeryState Key Laboratory of Natural MedicinesJiangsu Key Laboratory of Druggability of BiopharmaceuticalsSchool of Life Science and TechnologyChina Pharmaceutical UniversityNanjingChinaDepartment of Joint SurgeryHonghui HospitalXi'an Jiaotong UniversityXi'an ChinaDepartment of Orthopedics SurgeryTrauma Medical CentreWest China Hospital, Sichuan UniversityChengduChinaDepartment of Orthopedics SurgeryTrauma Medical CentreWest China Hospital, Sichuan UniversityChengduChinaDepartment of Orthopedics SurgeryTrauma Medical CentreWest China Hospital, Sichuan UniversityChengduChinaDepartment of Orthopedics SurgeryTrauma Medical CentreWest China Hospital, Sichuan UniversityChengduChinaDepartment of Joint SurgeryHonghui HospitalXi'an Jiaotong UniversityXi'an ChinaDepartment of GynecologyWest China Second Hospital, Sichuan UniversityChengduChinaAbstract Background Hypoxia can affect the occurrence and development of inflammation in humans, but its effects on the disease progression of osteoarthritis (OA) remain unclear. Synovial macrophages play an essential role in the progression of arthritis. Specifically, the activation of the NOD‐like receptor family pyrin domain containing 3 (NLRP3) in macrophages induces the secretion of a series of inflammatory factors, accelerating the progression of OA. Methods The effects of CBR‐470‐1 were assessed in a mouse model of OA induced by destabilization of the medial meniscus (DMM) by micro‐computed tomography imaging, Safranin‐O and Fast Green staining, immunofluorescence staining and enzyme‐linked immunosorbent assay. Western Blot analysis was used to explore the underlying mechanism of these experimental results. Additionally, a co‐culture system of THP‐1 and chondrocytes was established to investigate the impact of CBR‐470‐1 on chondrocyte proliferation, apoptosis, migration and the regulation of chondrocyte‐related proteins within the system. Results In hypoxic conditions, CBR‐470‐1 significantly inhibited the progression of OA in the DMM‐induced OA mouse model, but that effect disappeared in the DMM‐induced OA phosphoglycerate kinase 1 (PGK1)fl/flLyz2‐Cre mouse model. Not only that, CBR‐470‐1 can also improve the proliferation and migration of chondrocytes, reduce the apoptosis rate of chondrocytes, and regulate the expression of chondrocyte‐related proteins in the co‐culture system of THP‐1 and chondrocytes. Conclusions This study conducted a series of in vitro and in vivo experiments, revealing that hypoxia plays a pro‐inflammatory role by increasing PGK1 activity and reducing the binding of the deubiquitinating enzyme ubiquitin‐specific peptidase 14 to NLRP3, thereby reducing the ubiquitination level of NLRP3. CBR‐470‐1, a specific inhibitor of PGK1, can reduce PGK1 activity to reverse the role of hypoxia in the progression of OA. These findings lay a foundation for the development of OA treatment in a hypoxic environment. Key points Hypoxia plays a pro‐inflammatory role by increasing PGK1 activity and thereby decreasing the ubiquitination level of NLRP3. Hypoxia plays a pro‐inflammatory role by increasing PGK1 activity, reducing the binding of the deubiquitinating enzyme USP14 to NLRP3, and reducing the ubiquitination level of NLRP3. CBR‐470‐1 reverses the role of hypoxia in the progression of osteoarthritis.https://doi.org/10.1002/ctm2.70118CBR‐470‐1hypoxiaNLRP3osteoarthritisPGK1USP14 |
| spellingShingle | Ao Duan Zemeng Ma Xiaolong Shao Zhencheng Xiong Chaoyi Zhang Wenzheng Liu Guanglin Wang Shouye Hu Wei Lin The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity Clinical and Translational Medicine CBR‐470‐1 hypoxia NLRP3 osteoarthritis PGK1 USP14 |
| title | The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity |
| title_full | The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity |
| title_fullStr | The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity |
| title_full_unstemmed | The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity |
| title_short | The antiarthritic effect of CBR‐470‐1 in hypoxic environment is to increase the level of NOD‐like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity |
| title_sort | antiarthritic effect of cbr 470 1 in hypoxic environment is to increase the level of nod like receptor family pyrin domain containing 3 ubiquitination by decreasing phosphoglycerate kinase 1 activity |
| topic | CBR‐470‐1 hypoxia NLRP3 osteoarthritis PGK1 USP14 |
| url | https://doi.org/10.1002/ctm2.70118 |
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