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Die mechanistische Untersuchung des altersbedingten Del-1-Mangels bei der Auflösung einer chronisch-entzündlichen Parodontitis

Antragsteller Jong-Hyung Lim, Ph.D.
Fachliche Zuordnung Zahnheilkunde; Mund-, Kiefer- und Gesichtschirurgie
Immunologie
Public Health, Gesundheitsbezogene Versorgungsforschung, Sozial- und Arbeitsmedizin
Förderung Förderung von 2018 bis 2022
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 417757362
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

Periodontal ligament mesenchymal stem cells (referred to as PDL-MSCs) in bone tissue have the remarkable ability to proliferate and undergo osteogenic differentiation, which contributes to the maintenance and regeneration of periodontal tissues. However, in aging-associated pathologies like periodontitis, dysfunction of PDL-MSCs may occur. Despite this knowledge, the molecular mechanisms responsible for age-related dysfunction of PDL-MSCs during the resolution of periodontitis are not fully understood. One promising candidate in this context is Del-1 (developmental endothelial locus-1), an endogenously expressed protein known to exert anti-inflammatory effects and regulate the initiation and resolution of inflammation in various diseases, including periodontitis. Recent evidence suggests that Del-1 is highly expressed by MSCs and that its expression is downregulated in aging tissues in both humans and mice. Interestingly, immunohistochemical staining detected Del-1 expression in the periodontal ligament, where osteogenic progenitor cells such as MSCs are localized. Thus, in this study, our aim was to investigate whether Del-1 can promote the proliferation and osteogenic differentiation of PDL-MSCs, potentially leading to increased bone regeneration during the resolution of experimental periodontitis in aging individuals. In this study, we observed that the local administration of exogenous DEL-1-Fc to 12- month-old mice during the resolution of ligature-induced periodontitis promotes bone gain compared to the Fc control group. In our in vitro experiments, we found that treatment with DEL-1-Fc enhances the osteogenic differentiation of MSCs compared to the Fc control group. Additionally, Del-1-deficient MSCs were associated with defective osteogenesis compared to Del-1-sufficient MSCs. Furthermore, we observed a higher number of Ki67+ MSCs in the DEL-1-Fc-treated group, indicating that DEL-1 promotes MSC proliferation in vitro. Moreover, aged MSCs tend to undergo senescence, which can contribute to dysfunction in bone regeneration. Strikingly, DEL-1 inhibited oxidative stress-induced BMSC senescence, reducing the expression of p16 and p21 and reducing granularity, which was also reproducible in naturally aged BMSCs in vitro. In Del1KO mice, naturally occurring bone loss with age was exacerbated compared to WT ctrl mice. Del1KO mice showed increased expression of senescence-related genes including p21, p53, Cxcl2, IL6, and an increased number of senescent BMSCs compared to WT littermates. Together, these results suggest that DEL-1 promotes the proliferation and osteogenic differentiation of PDL-MSCs while inhibiting senescence, potentially leading to alveolar bone regeneration in aging-associated periodontitis. These findings indicate that DEL-1 may hold therapeutic potential for restoring age-mediated bone loss.

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