Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade
Abstract Background Periprosthetic osteolysis and subsequent aseptic loosening are the leading causes of failure following total joint arthroplasty. Osteogenic impairment induced by wear particles is regarded as a crucial contributing factor in the development of osteolysis, with endoplasmic reticul...
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BMC
2024-12-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-024-01034-z |
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| author | Xin Yu Juan Jiang Cheng Li Yang Wang Zhengrong Ren Jianlun Hu Tao Yuan Yongjie Wu Dongsheng Wang Ziying Sun Qi Wu Bin Chen Peng Fang Hao Ding Jia Meng Hui Jiang Jianning Zhao Nirong Bao |
| author_facet | Xin Yu Juan Jiang Cheng Li Yang Wang Zhengrong Ren Jianlun Hu Tao Yuan Yongjie Wu Dongsheng Wang Ziying Sun Qi Wu Bin Chen Peng Fang Hao Ding Jia Meng Hui Jiang Jianning Zhao Nirong Bao |
| author_sort | Xin Yu |
| collection | DOAJ |
| description | Abstract Background Periprosthetic osteolysis and subsequent aseptic loosening are the leading causes of failure following total joint arthroplasty. Osteogenic impairment induced by wear particles is regarded as a crucial contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress identified as a key underlying mechanism. Therefore, identifying potential therapeutic targets and agents that can regulate ER stress adaption in osteoblasts is necessary for arresting aseptic loosening. Osthole (OST), a natural coumarin derivative, has demonstrated promising osteogenic properties and the ability to modulate ER stress adaption in various diseases. However, the impact of OST on ER stress-mediated osteogenic impairment caused by wear particles remains unclear. Methods TiAl6V4 particles (TiPs) were sourced from the prosthesis of patients who underwent revision hip arthroplasty due to aseptic loosening. A mouse calvarial osteolysis model was utilized to explore the effects of OST on TiPs-induced osteogenic impairment in vivo. Primary mouse osteoblasts were employed to investigate the impact of OST on ER stress-mediated osteoblast apoptosis and osteogenic inhibition induced by TiPs in vitro. The mechanisms underlying OST-modulated alleviation of ER stress induced by TiPs were elucidated through Molecular docking, immunochemistry, PCR, and Western blot analysis. Results In this study, we found that OST treatment effectively mitigated TiAl6V4 particles (TiPs)-induced osteolysis by enhancing osteogenesis in a mouse calvarial model. Furthermore, we observed that OST could attenuate ER stress-mediated apoptosis and osteogenic reduction in osteoblasts exposed to TiPs in vitro and in vivo. Mechanistically, we demonstrated that OST exerts bone-sparing effects on stressed osteoblasts upon TiPs exposure by specifically suppressing the ER stress-dependent PERK signaling cascade. Conclusion Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade. These findings suggest that OST may serve as a potential therapeutic agent for combating wear particle-induced osteogenic impairment, offering a novel alternative strategy for managing aseptic prosthesis loosening. |
| format | Article |
| id | doaj-art-1db7541146d54e5b9afcf2a60182b294 |
| institution | DOAJ |
| issn | 1528-3658 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Molecular Medicine |
| spelling | doaj-art-1db7541146d54e5b9afcf2a60182b2942025-08-20T02:39:40ZengBMCMolecular Medicine1528-36582024-12-0130112610.1186/s10020-024-01034-zOsthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascadeXin Yu0Juan Jiang1Cheng Li2Yang Wang3Zhengrong Ren4Jianlun Hu5Tao Yuan6Yongjie Wu7Dongsheng Wang8Ziying Sun9Qi Wu10Bin Chen11Peng Fang12Hao Ding13Jia Meng14Hui Jiang15Jianning Zhao16Nirong Bao17Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityState Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing UniversityDepartment of Spine Surgery, Center of Orthopedics, Daping Hospital, Army Medical University (Third Military Medical University)Department of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Vascular Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua UniversityBerlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff InstituteDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Orthopedics, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityAbstract Background Periprosthetic osteolysis and subsequent aseptic loosening are the leading causes of failure following total joint arthroplasty. Osteogenic impairment induced by wear particles is regarded as a crucial contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress identified as a key underlying mechanism. Therefore, identifying potential therapeutic targets and agents that can regulate ER stress adaption in osteoblasts is necessary for arresting aseptic loosening. Osthole (OST), a natural coumarin derivative, has demonstrated promising osteogenic properties and the ability to modulate ER stress adaption in various diseases. However, the impact of OST on ER stress-mediated osteogenic impairment caused by wear particles remains unclear. Methods TiAl6V4 particles (TiPs) were sourced from the prosthesis of patients who underwent revision hip arthroplasty due to aseptic loosening. A mouse calvarial osteolysis model was utilized to explore the effects of OST on TiPs-induced osteogenic impairment in vivo. Primary mouse osteoblasts were employed to investigate the impact of OST on ER stress-mediated osteoblast apoptosis and osteogenic inhibition induced by TiPs in vitro. The mechanisms underlying OST-modulated alleviation of ER stress induced by TiPs were elucidated through Molecular docking, immunochemistry, PCR, and Western blot analysis. Results In this study, we found that OST treatment effectively mitigated TiAl6V4 particles (TiPs)-induced osteolysis by enhancing osteogenesis in a mouse calvarial model. Furthermore, we observed that OST could attenuate ER stress-mediated apoptosis and osteogenic reduction in osteoblasts exposed to TiPs in vitro and in vivo. Mechanistically, we demonstrated that OST exerts bone-sparing effects on stressed osteoblasts upon TiPs exposure by specifically suppressing the ER stress-dependent PERK signaling cascade. Conclusion Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade. These findings suggest that OST may serve as a potential therapeutic agent for combating wear particle-induced osteogenic impairment, offering a novel alternative strategy for managing aseptic prosthesis loosening.https://doi.org/10.1186/s10020-024-01034-zOstholeAseptic looseningOsteolysisOsteoblastER stressPERK signaling cascade |
| spellingShingle | Xin Yu Juan Jiang Cheng Li Yang Wang Zhengrong Ren Jianlun Hu Tao Yuan Yongjie Wu Dongsheng Wang Ziying Sun Qi Wu Bin Chen Peng Fang Hao Ding Jia Meng Hui Jiang Jianning Zhao Nirong Bao Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade Molecular Medicine Osthole Aseptic loosening Osteolysis Osteoblast ER stress PERK signaling cascade |
| title | Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade |
| title_full | Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade |
| title_fullStr | Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade |
| title_full_unstemmed | Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade |
| title_short | Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade |
| title_sort | osthole ameliorates wear particle induced osteogenic impairment by mitigating endoplasmic reticulum stress via perk signaling cascade |
| topic | Osthole Aseptic loosening Osteolysis Osteoblast ER stress PERK signaling cascade |
| url | https://doi.org/10.1186/s10020-024-01034-z |
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