Senescent periodontal ligament cells as a potential therapeutic target for age-associated periodontitis

/Abstract Periodontal disease (PD) is a leading cause of tooth loss in adults. The mechanisms by which aging increases PD bone loss are unknown. Treating PD costs $3.49B in the US in 2018, and socio-economic burden of PD is projected to increase. Thus, there is an urgent need to develop therapeutics to overcome PD. Excess bone resorption and reduced bone formation are mechanisms of PD bone loss. In young mice, we showed that ligature-induced PD (LIP) caused transient bone resorption followed by bone formation, resulting in limited LIP bone loss. Conversely, we found that while resorptive patterns were similar in mature mice, bone loss in LIP could not be recovered due to impaired bone formation, suggesting that reduced osteogenic capability with age is a mechanism for increased PD bone loss in adults. Previous studies demonstrated that aging in osteoprogenitors reduced bone formation in long bones. However, this mechanism has not yet been tested in the osteoprogenitors in periodontal ligaments (PDLs), the major source of periodontal osteoprogenitors. Cellular senescence is a driver of aging. Senescent cells (SCs) are induced by biological stresses and persist in tissue via upregulation of senescent cell antiapoptotic pathways (SCAPs). Accumulation of SCs causes depletion of tissue progenitors and defective tissue regeneration. Genetic ablation of SCs improved bone formation and bone mass in aged mice, demonstrating that senolysis could be a therapeutic approach for age-associated bone loss. We identified SCs in PDLs of mature mice. However, whether removing PDL SCs could prevent age-associated PD bone loss has yet to be addressed. Pharmacological removal of SCs using senolytics, drugs that suppress SCAPs, has been proposed to alleviate the negative impacts of SCs. The efficacy of varying senolytic treatments varies between tissues because of heterogeneity in active SCAPs. We tested senolytic efficacy in mouse periodontal tissue and support the notion that identifying appropriate senolytic drugs is crucial to treating a specific disease by senolytics. The senolytics effective for human PDL cells (hPDLCs) have not yet been identified. We hypothesize that aging in PDLs diminishes alveolar bone recovery through senescence-mediated functional defects in osteoprogenitors, and removing SCs from PDLs will be an effective therapeutic approach to reverse the aging effect and protect alveolar bone from age-associated PD bone loss. We propose the following aims: Aim 1. Determine whether premature aging in PDLs decreases alveolar bone recovery from PD bone loss. We will genetically induce premature aging in PDLs of young mice (Plap1-CreERT2/Zmpste24fl/fl) and analyze its impact on periodontal osteogenesis. Aim 2. Determine if PDL- targeted senolysis restores decreased bone recovery in mature mice. We will ablate SCs in PDLs of mature mice by inducing SC apoptosis (Plap1-CreERT2/p16INK-LOX-ATTAC) and test the impact of the senolysis on periodontal osteogenesis. Aim 3. Identify senolytic drug(s) effective for senescent hPDLCs. We will treat senescent hPDLCs with senolytics targeting varied SCAPs to identify senolytic(s) effective for hPDLCs. Project Number: 1R01DE034757-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Mizuho Kittaka | Institution: AUGUSTA UNIVERSITY, AUGUSTA, GA | Award Amount: $385,116 | Activity Code: R01 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11106582