ORIGINAL RESEARCH article
Front. Cell. Infect. Microbiol.
Sec. Bacteria and Host
Volume 15 - 2025 | doi: 10.3389/fcimb.2025.1614126
Gingipains disrupt bone homeostasis via dual regulation of osteogenesis and osteoclastogenesis through exosomal miR-146a-5p/TRAF6 signaling
Provisionally accepted
- 1Department of Periodontology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 2National Oral Disease Clinical Medicine Research Center, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Background Gingipains are virulence factors released by Porphyromonas gingivalis that contribute to periodontal destruction by disrupting bone metabolism. This study aimed to evaluate the dual effects of gingipains on bone metabolism by examining their impact on osteogenesis and osteoclastogenesis, hypothesizing that gingipains regulate these processes via direct and exosomal pathways involving microRNA signaling.Methods Clinical samples of gingival crevicular fluid, subgingival plaque, and gingival tissues were collected from 15 patients with stage III-IV periodontitis and 15 healthy controls. The effects of gingipains on bone marrow mesenchymal stem cells (BMSCs) and RAW264.7 macrophages were assessed using cell proliferation assays, qPCR, western blot, microarray analysis, and dual-luciferase reporter assays. A rat periodontitis model was used to validate the findings in vivo.Periodontitis patients exhibited elevated levels of lysine-and arginine-specific gingipains, C5a, and RANKL (p < 0.05). Gingipains inhibited BMSCs proliferation and osteogenic differentiation in a dose-dependent manner while promoting osteoclastogenesis in RAW264.7 macrophages through BMSCs-derived exosomes.Gingipains reduced the levels of miR-146a-5p in exosomes, which enhanced osteoclast differentiation through the miR-146a-5p/TRAF6 signaling pathway. Animal models confirmed that gingipains aggravated alveolar bone loss, which was mitigated by miR-146a-5p overexpression.and promoting osteoclastogenesis through communication via exosomes. Targeting miR-146a-5p offers a potential therapeutic approach to counter gingipain-induced periodontal destruction.
Keywords: Gingipains, Kgp, RGP, Osteoclastic differentiation, MiR-146a-5p, TRAF6
Received: 18 Apr 2025; Accepted: 19 Jul 2025.
Copyright: © 2025 Dong, Liao, Sun, Chen, Zhou, Zhang, Zhou and Song. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhongchen Song, Department of Periodontology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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