By combining in vivo ligature-induced periodontitis mouse model in CD73-deficient animals with ex vivo and in vitro cell analysis comparing WT and CD73-deficient cells, we showed higher levels of pro-inflammatory markers in local gingiva with decreased healing capacity and higher levels of MMP-13 in CD73-deficient stromal fibroblasts, revealing a hyper-inflammatory profile in gingival fibroblasts as a consequence of the lack of CD73. This evidence concerns the gene NT5E and periodontitis.