The role of cellular senescence in bone loss and recovery in periodontal disease

Project Summary/Abstract The prevalence of tooth-supporting alveolar bone loss by periodontal disease (PD) steeply rises in the 3rd and 4th decades of life. As such, PD is a leading cause of tooth loss in adults. Mechanisms behind the increased susceptibility to PD bone loss in adulthood are unknown. 17 to 23% of PD patients do not respond to current treatment and thus progress to tooth loss. Our long-term goal is to identify the mechanism of age-related bone loss in PD to develop mechanistically based therapies of PD bone loss. A potential factor in the development of PD bone loss is the accumulation of senescent cells. Senescent cell accumulation in tissues is increasingly recognized as a driver of age-associated disorders. To mitigate the deleterious effects, senescent cells can be removed by drugs called senolytics that selectively induce apoptosis in senescent cells. Fisetin is a recently characterized senolytic without observable adverse effects and is being evaluated in clinical trials targeting pathological conditions hallmarked by senescent cell burden. Our preliminary studies using the ligature-induced PD (LIP) model showed that LIP induces initial rapid bone resorption followed by a rapid recovery due to bone formation by day 14 in young mice (2.5 months). In contrast, significant bone loss remained at day 14 in mature mice (8-12 months). Also, mature mice showed greater bone volume loss compared to young mice, indicating the increased susceptibility to LIP-induced bone loss in mature mice. Furthermore, bone formation rate in mature mice with LIP was lower than young mice, suggesting that diminished bone formation rate is responsible for the increased susceptibility to LIP-induced bone loss in mature mice. We found increases in expression levels of senescence marker genes in periodontal tissue of mature mice before PD induction, suggesting that accumulation of senescent cells in the tissue increase the susceptibility to LIP-induced bone loss in mature mice. Our hypothesis is that accumulation of the senescent cells is a critical factor responsible for inhibiting bone recovery and for increasing bone loss susceptibility in the pathology of PD bone loss, and that senolytic treatment will improves the PD-driven bone loss. Here, we propose the following aims: Specific Aim 1: Determine if the clearance of pre-existing senescent cells by the senolytic, fisetin, will prevent PD alveolar bone loss. 12-month-old mice will be pre- treated with fisetin to clear and prevent age-related senescent accumulation before inducing LIP, and we will analyze the effect of senescent cell clearance by fisetin pre-treatment on LIP-induced bone loss. Specific Aim 2: Determine if fisetin treatment will induce recovery from PD-induced bone loss. We will induce LIP in 12- months-old mice and wait until bone resorption progress to detectable levels before starting fisetin treatment. We will then analyze bone loss induced by LIP. Our team is uniquely suited to conduct these experiments with expertise in periodontology, bone biology, and cellular senescence in musculoskeletal tissue. Outcomes from this work will lead us to further mechanistic studies of the role of senescence in PD toward our long-term goal.