Metabolic-Purinergic fitness in periodontal health and disease - Project Summary Despite periodontitis typically manifesting in later stages of life, our understanding of the mediators and biomarkers linked to severe disease manifestation and hyper-inflammatory responses leading to osteolytic destruction remains limited. In this context, the role of nucleotide-metabolizing enzymes, such as ecto-5’- nucleotidase (NT5E), or CD73, in characterizing purinergic influence on inflammatory alveolar bone loss remains largely unexplored. During the inflammatory process, there is an increase in extracellular ATP (eATP), and CD73 serves as the final step in converting eATP to adenosine (ADO) aiming to restore homeostasis. Our recent findings have illuminated the critical role of CD73-dependent ADO in controlling inflammation-associated state in gingival fibroblasts, implicating mitochondrial metabolism as a central mechanism in the pathogenesis of hyper-inflammatory gingival responses. Furthermore, our research has revealed that CD73-/- mice exhibit more aggressive alveolar bone loss in a ligature-induced periodontitis model. We observed a heightened proinflammatory state in murine primary gingival fibroblasts and a more aggressive osteoclast phenotype in mice lacking CD73 due to their increased mitochondrial activity. Our strong preliminary data have led us to hypothesize that ectonucleotidase CD73 in fibroblasts directs the metabolic capabilities of a stromal-osteoclast axis, due to increased migration and retention of osteoclast precursors leading to excessive bone resorption in periodontal pathogenesis. This hypothesis will be investigated through two Specific Aims: Specific aim 1 will delineate how CD73 deficiency leads to metabolic dysfunctional inflammation-associated gingival fibroblast state and define the link to osteoclast hyper-function. Since mitochondrial dysfunction is one of the hallmarks of ageing, age is incorporated as a biological variable. Specific aim 2 will study whether metabolic dysfunction drives an imbalance in the purinergic fitness and energy metabolism influencing a stromal-osteoclast axis in periodontium. Sex- related differences in metabolism of males and females will be considered. This research will lead to a comprehensive understanding of CD73 function in the periodontium as well as improve our knowledge of purinergic-metabolic relationship in periodontal health and disease. It will enable us to determine whether CD73 ectonucleotidase can be specifically targeted to manage periodontal homeostasis serving as a potential candidate for early diagnosis to prevent hyper-inflammatory responses.
