Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathway
Abstract Background Although increasing evidence confirms that oral microbiota imbalance is a critical factor inhibiting bone regeneration, the specific mechanisms have remained unexplored. This study aims to use periodontitis as a model of oral microbiota imbalance to investigate the specific mecha...
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BMC
2025-05-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03457-0 |
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| author | Xinghong Luo Yanzhen Wang Tingting Ning Qian Lei Hao Cui Xianghui Zou Yan Chen Shuoling Chen Xinyao Zhang Shenglong Tan Dandan Ma |
| author_facet | Xinghong Luo Yanzhen Wang Tingting Ning Qian Lei Hao Cui Xianghui Zou Yan Chen Shuoling Chen Xinyao Zhang Shenglong Tan Dandan Ma |
| author_sort | Xinghong Luo |
| collection | DOAJ |
| description | Abstract Background Although increasing evidence confirms that oral microbiota imbalance is a critical factor inhibiting bone regeneration, the specific mechanisms have remained unexplored. This study aims to use periodontitis as a model of oral microbiota imbalance to investigate the specific mechanisms that inhibit bone regeneration in extraction sockets. Methods Cone Beam Computed Tomography (CBCT) data of extraction sockets were collected from patients with and without periodontitis to confirm the influence of the periodontitis microenvironment on bone regeneration in extraction sockets. Furthermore, GW4869-pretreated Porphyromonas gingivalis (Pg) and normal Pg were used to build a periodontitis model, and then the bone regeneration in extraction sockets under these conditions was detected by H&E staining, Masson’s staining and micro-CT analysis. In vitro, the effect of Pg-derived OMVs on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) was examined. RNA sequencing, FerroOrange, malondialdehyde assay, transmission electron microscopy, qRT‒PCR, and western blotting analysis were performed. Results CBCT analysis showed that periodontitis significantly inhibited new bone formation in the extraction sockets in patients. Micro-CT and Histological analysis revealed that inhibiting OMVs released from Pg alleviated the inhibition of bone regeneration in extraction sockets under Pg imbalance. Moreover, Pg-derived OMVs treatment deteriorated bone regeneration in extraction sockets. In vitro, results showed that Pg-derived OMVs inhibited osteogenic differentiation of BMSCs. Furthermore, the results indicated a significant upregulation of ferroptosis in OMVs-treated BMSCs. Notably, targeting ferroptosis promoted osteogenic differentiation of BMSCs and bone regeneration in extraction sockets, as compared with the OMVs-treated group. Mechanistic studies have shown that Pg-derived OMVs promoted BMSCs ferroptosis via the Hippo- Yes-associated protein (YAP) pathway. Conclusion This study shows that a Pg microbiota imbalance inhibits bone regeneration by secreting OMVs from Pg to induce ferroptosis in BMSCs. Mechanically, we illustrated that OMVs induce ferroptosis through the Hippo-YAP pathway. These findings might provide a new insight and potential therapeutic target to promote bone regeneration under oral microbiota imbalance. Graphical Abstract |
| format | Article |
| id | doaj-art-7bbc26a304b542e68e6774732d3dd6f1 |
| institution | DOAJ |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Nanobiotechnology |
| spelling | doaj-art-7bbc26a304b542e68e6774732d3dd6f12025-08-20T03:07:54ZengBMCJournal of Nanobiotechnology1477-31552025-05-0123111910.1186/s12951-025-03457-0Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathwayXinghong Luo0Yanzhen Wang1Tingting Ning2Qian Lei3Hao Cui4Xianghui Zou5Yan Chen6Shuoling Chen7Xinyao Zhang8Shenglong Tan9Dandan Ma10Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical UniversityStomatological Hospital, School of Stomatology, Southern Medical UniversityDepartment of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical UniversityDepartment of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical UniversityStomatological Hospital, School of Stomatology, Southern Medical UniversityStomatological Hospital, School of Stomatology, Southern Medical UniversityDepartment of Pediatric Dentistry, Stomatological Hospital, School of Stomatology, Southern Medical UniversityStomatological Hospital, School of Stomatology, Southern Medical UniversityStomatological Hospital, School of Stomatology, Southern Medical UniversityDepartment of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical UniversityDepartment of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical UniversityAbstract Background Although increasing evidence confirms that oral microbiota imbalance is a critical factor inhibiting bone regeneration, the specific mechanisms have remained unexplored. This study aims to use periodontitis as a model of oral microbiota imbalance to investigate the specific mechanisms that inhibit bone regeneration in extraction sockets. Methods Cone Beam Computed Tomography (CBCT) data of extraction sockets were collected from patients with and without periodontitis to confirm the influence of the periodontitis microenvironment on bone regeneration in extraction sockets. Furthermore, GW4869-pretreated Porphyromonas gingivalis (Pg) and normal Pg were used to build a periodontitis model, and then the bone regeneration in extraction sockets under these conditions was detected by H&E staining, Masson’s staining and micro-CT analysis. In vitro, the effect of Pg-derived OMVs on osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) was examined. RNA sequencing, FerroOrange, malondialdehyde assay, transmission electron microscopy, qRT‒PCR, and western blotting analysis were performed. Results CBCT analysis showed that periodontitis significantly inhibited new bone formation in the extraction sockets in patients. Micro-CT and Histological analysis revealed that inhibiting OMVs released from Pg alleviated the inhibition of bone regeneration in extraction sockets under Pg imbalance. Moreover, Pg-derived OMVs treatment deteriorated bone regeneration in extraction sockets. In vitro, results showed that Pg-derived OMVs inhibited osteogenic differentiation of BMSCs. Furthermore, the results indicated a significant upregulation of ferroptosis in OMVs-treated BMSCs. Notably, targeting ferroptosis promoted osteogenic differentiation of BMSCs and bone regeneration in extraction sockets, as compared with the OMVs-treated group. Mechanistic studies have shown that Pg-derived OMVs promoted BMSCs ferroptosis via the Hippo- Yes-associated protein (YAP) pathway. Conclusion This study shows that a Pg microbiota imbalance inhibits bone regeneration by secreting OMVs from Pg to induce ferroptosis in BMSCs. Mechanically, we illustrated that OMVs induce ferroptosis through the Hippo-YAP pathway. These findings might provide a new insight and potential therapeutic target to promote bone regeneration under oral microbiota imbalance. Graphical Abstracthttps://doi.org/10.1186/s12951-025-03457-0Oral microbiota imbalanceOMVsBMSCsBone regenerationFerroptosis |
| spellingShingle | Xinghong Luo Yanzhen Wang Tingting Ning Qian Lei Hao Cui Xianghui Zou Yan Chen Shuoling Chen Xinyao Zhang Shenglong Tan Dandan Ma Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathway Journal of Nanobiotechnology Oral microbiota imbalance OMVs BMSCs Bone regeneration Ferroptosis |
| title | Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathway |
| title_full | Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathway |
| title_fullStr | Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathway |
| title_full_unstemmed | Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathway |
| title_short | Outer membrane vesicles of Porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the Hippo-YAP signaling pathway |
| title_sort | outer membrane vesicles of porphyromonas gingivalis impede bone regeneration by inducing ferroptosis via the hippo yap signaling pathway |
| topic | Oral microbiota imbalance OMVs BMSCs Bone regeneration Ferroptosis |
| url | https://doi.org/10.1186/s12951-025-03457-0 |
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