Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex
Osteoporosis affects around 200 million people globally, with menopausal women accounting for the bulk of cases. In the occurrence and development of osteoporosis, a key role is played by osteoclasts. Excessive osteoclast-mediated bone resorption activity reduces bone mass and increases bone fragili...
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| Format: | Article |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.896108/full |
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| author | Junchun Chen Junchun Chen Dezhi Song Dezhi Song Yang Xu Yang Xu Liwei Wu Liwei Wu Lili Tang Lili Tang YuanGang Su YuanGang Su Xiaoxiao Xie Xiaoxiao Xie Jinmin Zhao Jinmin Zhao Jiake Xu Qian Liu |
| author_facet | Junchun Chen Junchun Chen Dezhi Song Dezhi Song Yang Xu Yang Xu Liwei Wu Liwei Wu Lili Tang Lili Tang YuanGang Su YuanGang Su Xiaoxiao Xie Xiaoxiao Xie Jinmin Zhao Jinmin Zhao Jiake Xu Qian Liu |
| author_sort | Junchun Chen |
| collection | DOAJ |
| description | Osteoporosis affects around 200 million people globally, with menopausal women accounting for the bulk of cases. In the occurrence and development of osteoporosis, a key role is played by osteoclasts. Excessive osteoclast-mediated bone resorption activity reduces bone mass and increases bone fragility, resulting in osteoporosis. Thus, considerable demand exists for designing effective osteoporosis treatments based on targeting osteoclasts. Eltanexor (Elt; KPT-8602) is a selective nuclear-export inhibitor that covalently binds to and blocks the function of the nuclear-export protein exportin-1 (XPO1), which controls the nucleus-to-cytoplasm transfer of certain critical proteins related to growth regulation and tumor suppression, such as p53, IκBα [nuclear factor-κB (NF-κB) inhibitor α] and FOXO1; among these proteins, IκBα, a critical component of the NF-κB signaling pathway that primarily governs NF-κB activation and transcription. How Elt treatment affects osteoclasts remains poorly elucidated. Elt inhibited the growth and activity of RANKL-induced osteoclasts in vitro in a dose-dependent manner, and Elt exerted no cell-killing effect within the effective inhibitory concentration. Mechanistically, Elt was found to trap IκBα in the nucleus and thus protect IκBα from proteasome degradation, which resulted in the blocking of the translocation of IκBα and NF-κB p65 and the consequent inhibition of NF-κB activity. The suppression of NF-κB activity, in turn, inhibited the activity of two transcription factors (NFATc1 and c-Fos) essential for osteoclast formation and led to the downregulation of genes and proteins related to bone resorption. Our study thus provides a newly identified mechanism for targeting in the treatment of osteoporosis. |
| first_indexed | 2024-12-10T18:12:27Z |
| format | Article |
| id | doaj.art-c2c547d55ba94b0c842f31e026752279 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-10T18:12:27Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-c2c547d55ba94b0c842f31e0267522792022-12-22T01:38:25ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-08-011310.3389/fphar.2022.896108896108Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 ComplexJunchun Chen0Junchun Chen1Dezhi Song2Dezhi Song3Yang Xu4Yang Xu5Liwei Wu6Liwei Wu7Lili Tang8Lili Tang9YuanGang Su10YuanGang Su11Xiaoxiao Xie12Xiaoxiao Xie13Jinmin Zhao14Jinmin Zhao15Jiake Xu16Qian Liu17Research Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaCollaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaGuangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaGuangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaCollaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaCollaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaGuangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaCollaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, ChinaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaGuangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, ChinaSchool of Biomedical Sciences, The University of Western Australia, Perth, WA, AustraliaResearch Centre for Regenerative Medicine, Orthopaedic Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, ChinaOsteoporosis affects around 200 million people globally, with menopausal women accounting for the bulk of cases. In the occurrence and development of osteoporosis, a key role is played by osteoclasts. Excessive osteoclast-mediated bone resorption activity reduces bone mass and increases bone fragility, resulting in osteoporosis. Thus, considerable demand exists for designing effective osteoporosis treatments based on targeting osteoclasts. Eltanexor (Elt; KPT-8602) is a selective nuclear-export inhibitor that covalently binds to and blocks the function of the nuclear-export protein exportin-1 (XPO1), which controls the nucleus-to-cytoplasm transfer of certain critical proteins related to growth regulation and tumor suppression, such as p53, IκBα [nuclear factor-κB (NF-κB) inhibitor α] and FOXO1; among these proteins, IκBα, a critical component of the NF-κB signaling pathway that primarily governs NF-κB activation and transcription. How Elt treatment affects osteoclasts remains poorly elucidated. Elt inhibited the growth and activity of RANKL-induced osteoclasts in vitro in a dose-dependent manner, and Elt exerted no cell-killing effect within the effective inhibitory concentration. Mechanistically, Elt was found to trap IκBα in the nucleus and thus protect IκBα from proteasome degradation, which resulted in the blocking of the translocation of IκBα and NF-κB p65 and the consequent inhibition of NF-κB activity. The suppression of NF-κB activity, in turn, inhibited the activity of two transcription factors (NFATc1 and c-Fos) essential for osteoclast formation and led to the downregulation of genes and proteins related to bone resorption. Our study thus provides a newly identified mechanism for targeting in the treatment of osteoporosis.https://www.frontiersin.org/articles/10.3389/fphar.2022.896108/fulleltanexor (KPT-8602)selinexor (KPT-330)NF-κBXPO1osteoporosis |
| spellingShingle | Junchun Chen Junchun Chen Dezhi Song Dezhi Song Yang Xu Yang Xu Liwei Wu Liwei Wu Lili Tang Lili Tang YuanGang Su YuanGang Su Xiaoxiao Xie Xiaoxiao Xie Jinmin Zhao Jinmin Zhao Jiake Xu Qian Liu Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex Frontiers in Pharmacology eltanexor (KPT-8602) selinexor (KPT-330) NF-κB XPO1 osteoporosis |
| title | Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex |
| title_full | Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex |
| title_fullStr | Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex |
| title_full_unstemmed | Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex |
| title_short | Anti-Osteoclast Effect of Exportin-1 Inhibitor Eltanexor on Osteoporosis Depends on Nuclear Accumulation of IκBα–NF-κB p65 Complex |
| title_sort | anti osteoclast effect of exportin 1 inhibitor eltanexor on osteoporosis depends on nuclear accumulation of iκbα nf κb p65 complex |
| topic | eltanexor (KPT-8602) selinexor (KPT-330) NF-κB XPO1 osteoporosis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.896108/full |
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