Osteoarthritis
the contributions of MKK7–JNK in cartilage ageing and OA progression in response to mechanical stress are not known. 48 49 In the present study, we found that FBXW7 inhibition by exces- sive mechanical loading strongly elevated MKK7 expression and subsequently induced an increase in the JNK signal in chon- drocytes, resulting in enhanced cell senescence. Additionally, FBXW7 loss-induced chondrocyte senescence and cartilage degeneration were ameliorated by MKK7 inhibitor DTP3. These results indicate that the MKK7–JNK pathway plays an important role in mechanical stress-induced chondrocyte senescence and cartilage degeneration. To conclude, our study found an association between mechan- ical loading and cell senescence in OA development. FBXW7 loss and activation of MKK7–JNK signalling play a crucial role in biomechanically induced chondrocyte senescence. Overex- pression of FBXW7 by targeting its transcriptional regulators or upstream lncRNAs, or targeting MKK7 by DTP3 might repre- sent novel therapeutic approaches for OA treatment. Author affiliations 1 Department of Orthopedics, Academy of Orthopedics·Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China 2 Department of Joint Surgery, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third School of Clinical Medicine, Southern Medical University, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China 3 Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, Guangdong, China Contributors HyZ and XB conceived the ideas for experimental designs, analysed data and wrote the manuscript. HyZ and YS conducted the majority of the experiments and helped with manuscript preparation. ZY conducted the majority of the experiments and analysed data during the revision of the article. CZ, HbZ and LL performed immunohistochemistry and immunofluorescence and confocal imaging. HbZ and KL conducted cell cultures and western blot experiments. JY and ZY collected human tissue samples. CZ, XB and DC developed the concept, supervised the project and conceived the experiments. All authors approved the final version of the manuscript. XB accepted full responsibility for the finished work, had access to the data and controlled the decision to publish. Funding This work was supported by grants from the National Natural Science Foundation of China (grant numbers 81974341, 81991510 and 81991511) and the Natural Science Foundation of Guangdong Province (2020A1515011062). Competing interests None declared. Patient consent for publication Consent obtained directly from patient(s) Ethics approval This study involves human participants, and patient consent and the approval of the ethics committee of the Third Affiliated Hospital of Southern Medical University (Guangzhou, China) were obtained before the human tissue samples were harvested (201711001). Participants gave informed consent to participate in the study before taking part. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available in a public, open access repository. Not applicable. Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. ORCID iDs
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Guozhi Xiao http://orcid.org/0000-0002-4269-2450 Daozhang Cai http://orcid.org/0000-0002-8232-8194 Xiaochun Bai http://orcid.org/0000-0001-9631-4781
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