The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2
Abstract Background Periodontitis is a chronic inflammatory disease that significantly impacts periodontal bone regeneration, yet the distinct biological features of osteoblasts in this condition remain poorly understood. This study aims to elucidate the cellular and molecular mechanisms underlying...
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BMC
2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06569-1 |
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| author | Rui Dong Meihui Li Xiu Feng Gu Haiting Gao Ziyi Wei Houbao Qi Jun Zhang Qiang Feng |
| author_facet | Rui Dong Meihui Li Xiu Feng Gu Haiting Gao Ziyi Wei Houbao Qi Jun Zhang Qiang Feng |
| author_sort | Rui Dong |
| collection | DOAJ |
| description | Abstract Background Periodontitis is a chronic inflammatory disease that significantly impacts periodontal bone regeneration, yet the distinct biological features of osteoblasts in this condition remain poorly understood. This study aims to elucidate the cellular and molecular mechanisms underlying osteoblast dysfunction in periodontitis, with a focus on the role of Fusobacterium nucleatum (Fn) and its effector protein, D-galactose-binding periplasmic protein (Gbp). Method Single-cell RNA sequencing (scRNA-seq) data from human gingival tissues of periodontitis patients (PD) and healthy controls (HC) were analyzed to identify cellular heterogeneity and molecular pathways. An experimental periodontitis model in mice and primary osteoblast cultures were used to investigate the effects of Fn and Gbp on osteogenic differentiation. Transcriptomic analysis, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were employed to explore the underlying mechanisms. Results scRNA-seq revealed a reduction in mesenchymal stem cells (MSCs) and osteoblastic lineage cells in PD tissues, with significant downregulation of osteogenic pathways such as Wnt signaling. Fn infection induced alveolar bone destruction in vivo and inhibited osteoblast proliferation, differentiation, and mineralization in vitro. Gbp, an Fn adhesin, similarly impaired osteogenic differentiation by downregulating key osteogenic genes and pathways. Transcriptomic analysis identified shared inflammatory and osteogenic pathways affected by Fn and Gbp, with NF-κB signaling activated and Wnt/β-catenin signaling inhibited. Mechanistically, Gbp interacted with the host protein ANXA2, disrupting the ANXA2/GSK3β complex and inhibiting Wnt/β-catenin signaling, a pivotal route for osteoblast differentiation. ANXA2 knockdown mitigated the Fn/Gbp-induced suppression of osteogenic activity, emphasizing its role in Fn-induced bone loss. Conclusion This study demonstrates that Fn and its effector Gbp disrupt osteogenic differentiation by inactivating the Wnt/β-catenin pathway binding to ANXA2. |
| format | Article |
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| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-03771d06e7d9452ea47c8af55b6c04392025-08-20T01:51:28ZengBMCJournal of Translational Medicine1479-58762025-05-0123111810.1186/s12967-025-06569-1The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2Rui Dong0Meihui Li1Xiu Feng Gu2Haiting Gao3Ziyi Wei4Houbao Qi5Jun Zhang6Qiang Feng7Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Shandong UniversityDepartment of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong UniversityDepartment of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong UniversityDepartment of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong UniversityDepartment of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong UniversityDepartment of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong UniversityDepartment of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Shandong UniversityDepartment of Human Microbiome, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Shandong UniversityAbstract Background Periodontitis is a chronic inflammatory disease that significantly impacts periodontal bone regeneration, yet the distinct biological features of osteoblasts in this condition remain poorly understood. This study aims to elucidate the cellular and molecular mechanisms underlying osteoblast dysfunction in periodontitis, with a focus on the role of Fusobacterium nucleatum (Fn) and its effector protein, D-galactose-binding periplasmic protein (Gbp). Method Single-cell RNA sequencing (scRNA-seq) data from human gingival tissues of periodontitis patients (PD) and healthy controls (HC) were analyzed to identify cellular heterogeneity and molecular pathways. An experimental periodontitis model in mice and primary osteoblast cultures were used to investigate the effects of Fn and Gbp on osteogenic differentiation. Transcriptomic analysis, gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) networks were employed to explore the underlying mechanisms. Results scRNA-seq revealed a reduction in mesenchymal stem cells (MSCs) and osteoblastic lineage cells in PD tissues, with significant downregulation of osteogenic pathways such as Wnt signaling. Fn infection induced alveolar bone destruction in vivo and inhibited osteoblast proliferation, differentiation, and mineralization in vitro. Gbp, an Fn adhesin, similarly impaired osteogenic differentiation by downregulating key osteogenic genes and pathways. Transcriptomic analysis identified shared inflammatory and osteogenic pathways affected by Fn and Gbp, with NF-κB signaling activated and Wnt/β-catenin signaling inhibited. Mechanistically, Gbp interacted with the host protein ANXA2, disrupting the ANXA2/GSK3β complex and inhibiting Wnt/β-catenin signaling, a pivotal route for osteoblast differentiation. ANXA2 knockdown mitigated the Fn/Gbp-induced suppression of osteogenic activity, emphasizing its role in Fn-induced bone loss. Conclusion This study demonstrates that Fn and its effector Gbp disrupt osteogenic differentiation by inactivating the Wnt/β-catenin pathway binding to ANXA2.https://doi.org/10.1186/s12967-025-06569-1Fusobacterium nucleatumOsteogenic differentiationGbpANXA2 |
| spellingShingle | Rui Dong Meihui Li Xiu Feng Gu Haiting Gao Ziyi Wei Houbao Qi Jun Zhang Qiang Feng The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2 Journal of Translational Medicine Fusobacterium nucleatum Osteogenic differentiation Gbp ANXA2 |
| title | The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2 |
| title_full | The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2 |
| title_fullStr | The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2 |
| title_full_unstemmed | The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2 |
| title_short | The surface protein Gbp of Fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2 |
| title_sort | surface protein gbp of fusobacterium nucleatum inhibits osteogenic differentiation by inactivating the wnt β catenin pathway via binding to annexin a2 |
| topic | Fusobacterium nucleatum Osteogenic differentiation Gbp ANXA2 |
| url | https://doi.org/10.1186/s12967-025-06569-1 |
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