The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction
Abstract Receptor activator of nuclear factor kappa-B ligand (RANKL) initiates a complex signaling cascade that is crucial for inducing osteoclast differentiation and activation. RANKL-induced signaling has been analyzed in detail, and the involvement of TNF receptor-associated factor 6 (TRAF6), cal...
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BMC
2025-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-02021-x |
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| author | Kecheng Zhu Chunxiang Sheng Linlin Zhang Yuying Yang Xiaojing Chen Tao Jiang Jiaxi Song Deng Zhang Xiao Wang Hongyan Zhao Lihao Sun Libin Zhou Bei Tao Jianmin Liu |
| author_facet | Kecheng Zhu Chunxiang Sheng Linlin Zhang Yuying Yang Xiaojing Chen Tao Jiang Jiaxi Song Deng Zhang Xiao Wang Hongyan Zhao Lihao Sun Libin Zhou Bei Tao Jianmin Liu |
| author_sort | Kecheng Zhu |
| collection | DOAJ |
| description | Abstract Receptor activator of nuclear factor kappa-B ligand (RANKL) initiates a complex signaling cascade that is crucial for inducing osteoclast differentiation and activation. RANKL-induced signaling has been analyzed in detail, and the involvement of TNF receptor-associated factor 6 (TRAF6), calmodulin-dependent protein kinase (CaMK), NF-κB, mitogen-activated protein kinase (MAPK), activator protein-1 (AP-1), and molecules that contain an immunoreceptor tyrosine-based activation motif (ITAM) has been reported. However, the precise molecular steps that regulate RANKL signaling remain largely unknown. Here, we revealed the indispensable role of a class III histone deacetylase (SIRT5) in the processes of RANKL-induced osteoclast differentiation and activation. SIRT5 expression in osteoclasts was increased during osteoclastogenesis upon stimulation with RANKL. The RANKL-induced signaling activation was suppressed in SIRT5-deficient osteoclasts but enhanced by SIRT5 overexpression. Mice with global or conditional monocytic lineage knockout of SIRT5 had increased bone mass and reduced osteoclast numbers. In the cytoplasm, SIRT5 interacted with the scaffold protein JNK-interacting protein 4 (JIP4) to finely regulate MAPK signaling, which was critical for osteoclast differentiation and activation. Pharmacological inhibition of the catalytic activity of SIRT5 effectively reversed bone loss in ovariectomized mice. Taken together, the results of this study reveal that the SIRT5-JIP4 axis is a novel positive regulator that finely regulates RANKL-induced osteoclast differentiation and suggest that targeting this axis is a therapeutic strategy for preventing osteoporotic bone loss. Graphical Abstract |
| format | Article |
| id | doaj-art-c5d1a663f2ac4c468868a0b851d410db |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-c5d1a663f2ac4c468868a0b851d410db2025-01-19T12:33:02ZengBMCCell Communication and Signaling1478-811X2025-01-0123111910.1186/s12964-024-02021-xThe SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transductionKecheng Zhu0Chunxiang Sheng1Linlin Zhang2Yuying Yang3Xiaojing Chen4Tao Jiang5Jiaxi Song6Deng Zhang7Xiao Wang8Hongyan Zhao9Lihao Sun10Libin Zhou11Bei Tao12Jianmin Liu13Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAbstract Receptor activator of nuclear factor kappa-B ligand (RANKL) initiates a complex signaling cascade that is crucial for inducing osteoclast differentiation and activation. RANKL-induced signaling has been analyzed in detail, and the involvement of TNF receptor-associated factor 6 (TRAF6), calmodulin-dependent protein kinase (CaMK), NF-κB, mitogen-activated protein kinase (MAPK), activator protein-1 (AP-1), and molecules that contain an immunoreceptor tyrosine-based activation motif (ITAM) has been reported. However, the precise molecular steps that regulate RANKL signaling remain largely unknown. Here, we revealed the indispensable role of a class III histone deacetylase (SIRT5) in the processes of RANKL-induced osteoclast differentiation and activation. SIRT5 expression in osteoclasts was increased during osteoclastogenesis upon stimulation with RANKL. The RANKL-induced signaling activation was suppressed in SIRT5-deficient osteoclasts but enhanced by SIRT5 overexpression. Mice with global or conditional monocytic lineage knockout of SIRT5 had increased bone mass and reduced osteoclast numbers. In the cytoplasm, SIRT5 interacted with the scaffold protein JNK-interacting protein 4 (JIP4) to finely regulate MAPK signaling, which was critical for osteoclast differentiation and activation. Pharmacological inhibition of the catalytic activity of SIRT5 effectively reversed bone loss in ovariectomized mice. Taken together, the results of this study reveal that the SIRT5-JIP4 axis is a novel positive regulator that finely regulates RANKL-induced osteoclast differentiation and suggest that targeting this axis is a therapeutic strategy for preventing osteoporotic bone loss. Graphical Abstracthttps://doi.org/10.1186/s12964-024-02021-xSIRT5JIP4Osteoclast differentiationOsteoporosisRANKLMAPK |
| spellingShingle | Kecheng Zhu Chunxiang Sheng Linlin Zhang Yuying Yang Xiaojing Chen Tao Jiang Jiaxi Song Deng Zhang Xiao Wang Hongyan Zhao Lihao Sun Libin Zhou Bei Tao Jianmin Liu The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction Cell Communication and Signaling SIRT5 JIP4 Osteoclast differentiation Osteoporosis RANKL MAPK |
| title | The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction |
| title_full | The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction |
| title_fullStr | The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction |
| title_full_unstemmed | The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction |
| title_short | The SIRT5-JIP4 interaction promotes osteoclastogenesis by modulating RANKL-induced signaling transduction |
| title_sort | sirt5 jip4 interaction promotes osteoclastogenesis by modulating rankl induced signaling transduction |
| topic | SIRT5 JIP4 Osteoclast differentiation Osteoporosis RANKL MAPK |
| url | https://doi.org/10.1186/s12964-024-02021-x |
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