Sema3A Restores Bone Homeostasis in Peri-Implantitis by Activating Osteoblasts and Suppressing Osteoclasts via PI3K/AKT.

BACKGROUND

Peri-implantitis, a major cause of implant failure, is driven by disrupted bone homeostasis. Semaphorin 3A (Sema3A) bidirectionally regulates bone remodelling, yet its role in peri-implantitis remains poorly defined. This study aimed to elucidate the mechanisms by which Sema3A modulates bone homeostasis in peri-implantitis.

MATERIALS AND

METHODS

Single-cell transcriptomic analysis (GSE171213) was performed on a periodontitis-derived periodontal tissue dataset to characterize bone-related cell communication. A murine peri-implantitis model was established via silk ligation, and bone loss was assessed by micro‑CT. In vitro, MC3T3-E1 osteoblasts were exposed to Porphyromonas gingivalis LPS and transduced with Sema3A‑overexpressing lentivirus. Proliferation, migration, osteogenic differentiation, and the PI3K/AKT pathway were evaluated. An osteoblast-osteoclast coculture system was used to assess osteoclastogenesis.

RESULTS

Reanalysis of a periodontitis-derived single-cell dataset showed reduced SEMA3A expression and a lower osteogenic-lineage score in sparsely represented osteogenic-lineage-like cell populations under inflammatory conditions. Peri‑implantitis mice exhibited reduced SEMA3A, decreased P1NP, elevated CTX‑1, and significant bone loss (P < .05). Sema3A overexpression significantly rescued LPS‑impaired osteoblast proliferation, migration, and osteogenic differentiation (P < .01). RNA‑seq identified PI3K/AKT pathway enrichment; Sema3A increased phosphorylated AKT, and the PI3K/AKT inhibitor Palomid 529 abolished these protective effects. In coculture, Sema3A‑overexpressing osteoblasts suppressed osteoclast differentiation, reducing TRAP⁺ cells, Nfatc1, and Ctsk (P < .01).

CONCLUSIONS

Sema3A restores osteoblast function under inflammatory conditions, partly through PI3K/AKT signalling, and suppresses osteoclast differentiation indirectly in an osteoblast-osteoclast coculture system. Notably, Sema3A overexpression alone had no effect under normal conditions but specifically counteracted inflammatory damage. These findings suggest Sema3A is a potential therapeutic target for peri‑implantitis.

CLINICAL SIGNIFICANCE: Sema3A simultaneously enhances osteogenesis and inhibits bone resorption specifically under inflammatory conditions, while preserving basal bone homeostasis, thereby representing a targeted bone-protective strategy for peri-implantitis that may improve implant survival and reduce the need for invasive surgical interventions.