Possible Anti-inflammatory Roles of CD73 and Adenosine in Periapical Periodontitis
Objectives: Biologically relevant purine-chemicals, ATP and its metabolite adenosine (ADO), function as major energy currencies in cells. However, a paradigm shift in the study of purine biology occurred after it was discovered that receptors for extracellularly released ATP and ADO elicit proinflammatory and anti-inflammatory signals, respectively. Significantly, extracellular ATP released from activated neutrophils is converted to ADO via ectoenzymes, including ecto-5′-nucleotidase (CD73). However, the roles of CD73 and ADO in periapical-periodontitis are largely unknown. This study investigated the effects of CD73 and ADO on bone resorption induced in periapical-periodontitis of a mouse model. Methods: ADO receptor agonist 5′-(N-Ethylcarboxamido)-adenosine (NECA, 0.01mg/kg/day, i.p.) or control saline was systemically administered to C57BL/6 wild-type (WT) mice induced of periapical-periodontitis via pulp exposure (n=10/group). The impact of ADO loss-of-function was examined by comparison of pathogenic outcomes between CD73-Knock Out (KO) mice and WT mice (n=10/group), both with experimentally induced periapical lesion. Periapical tissues isolated from sacrificed mice at Day-21 were subjected to qPCR for CD73 and inflammatory bone resorption-related genes, while the amount of ATP and size of periapical-lesions were monitored using ATP detection kit and µCT. Results: The amount of ATP and CD73 mRNA were significantly increased in the mouse’s periapical lesion in a time-dependent manner. NECA-treated WT mice demonstrated significantly elevated mRNAs for CD73, alkaline phosphatase, and RUNX2, while showing decreased expressions of RANKL and IL1-β mRNAs, accompanied by diminished size of periapical lesion (0.11+0.02mm2), compared to nondrug-treated control WT mice (0.23+0.01mm2, P<0.05). The amount of ATP and mRNAs for RANKL, IL1-β, IL-6, and TNF-α, as well as the size of the periapical-lesion, were significantly elevated (P<0.05) in CD73-KO compared to the control WT mice. Conclusions: Catalytic conversion of ATP to ADO increases CD73 in the periapical lesion, resulting in downregulation of inflammatory bone loss, suggesting the CD73/ADO axis as a novel therapeutic target for periapical-periodontitis