Fgf2 Treatment as Potential Therapeutic Approach for Aging-Associated Periodontal Disease

Objectives: Periodontal disease (PD) is one of the most common and ageing-associated inflammatory diseases characterized by progressive destruction of periodontal tissues and alveolar bone, which ultimately leads to tooth loss. The development of diagnosis and treatments for aging-associated PD is currently hindered by the lack of understanding of the mechanisms that increase inflammation and exacerbate alveolar bone loss during aging.
Methods: To understand the mechanisms underlying how cell signaling changes result in an ageing-associated increased incidence of PD, we use RNA-seq transcriptomic analyses of periodontium isolated from young and aged WT mice (4 months (n=4), 12 months (n=2), and 22 months (n=3). We use Elisa assay to validate RNA-seq analysis results, generated PD mice through bacterial infection as an inflammatory disease model (n=5), and used adeno-associated virus (AAV)-mediated Fgf2 overexpression to study the function of Fgf2 in periodontal inflammation and bone resorption.
Results: Our unbiased RNA-seq data demonstrated that Fgfr2 signaling is upregulated in ageing-associated PD, as well as its downstream targets (PI3K-Akt, Ras/Erk, Tgfβ). RNA-seq results were validated by Elisa assay. Exogenous Fgf2 administration has been reported to be anti-inflammatory and enhance tissue regeneration. Local AAV-Fgf2 overexpression was confirmed by IHC staining. We found that Fgf2 overexpression reduced alveolar bone loss by 2-fold compared to PD AAV-YFP controls. Histological analysis demonstrated a 2-fold decrease in periodontal ligament width and mononuclear cell infiltration by H&E staining. Through IF staining, we show a 2-fold reduction in CD11c+ dendritic cells following local overexpression of Fgf2.
Conclusions: Taken together, our results indicated that AAV-Fgf2 simultaneously inhibits bone resorption and attenuates dendritic cell-mediated inflammation in aging-associated PD, potentially through its regulatory role in PI3K-Akt, Ras/Erk, Tgfβ signaling. Thus, Fgf2 may be a novel target for therapeutic approaches to attenuate inflammation and bone erosion in ageing-associated PD and other inflammation-related diseases.