CXXC5 Mediates <i>P. gingivalis</i>-suppressed Cementoblast Functions Partially via MAPK Signaling Network

Abstract

<i>Porphyromonas</i> (<i>P.) gingivalis</i> associates tightly with periodontal diseases and it is also a dominant pathogen of periapical periodontitis. However, the influence of <i>P. gingivalis</i> on cementoblasts, root surface cells pivotal in the apical areas, and the possible involvement of other molecules remain largely elusive. CXXC5 is a nuclear protein that regulates gene expression as well as cell growth, differentiation, and apoptosis. In this study, <i>P. gingivalis</i> repressed the mineralization capacity of cementoblasts by inducing inflammatory reactions and inhibiting cell differentiation. Intriguingly, the expression of CXXC5 decreased in <i>P. gingivalis</i>-treated OCCM-30 cells and apical periodontitis models but gradually increased during mineralization. Furthermore, RNA interference of CXXC5 significantly inhibited cementoblast differentiation, represented by decline of bone-associated markers Osterix, osteocalcin (OCN), and alkaline phosphatase (ALP). CXXC5 overexpression facilitated differentiation, and therefore attenuated the <i>P. gingivalis</i>-repressed effects on OCCM-30 cells. In addition, Erk1/2, p38, and PI3K-Akt were inactivated by silencing CXXC5 and activated upon its overexpression, whereas Wnt/β-catenin exhibited an opposite trend. The employment of specific inhibitors revealed that the CXXC5-dependent promotions of cementoblast differentiation were partially abrogated by p38 and PI3K-Akt inhibitors but were exacerbated by inhibiting Erk1/2. Overall, our experiment demonstrated a novel function of CXXC5 in the regeneration of impaired cementum caused by <i>P. gingivalis</i> invasion and suggested that MAPK signaling network balances the facilitation effects of CXXC5 in cementoblast differentiation.