Ckip-1 MediatesP. gingivalis–Suppressed Cementoblast Mineralization

Abstract

Porphyromonas gingivalis is responsible for the destruction of cementum in patients with periodontitis and periapical periodontitis. However, research about the effects of P. gingivalis on cementoblast mineralization and the underlying mechanism is still lacking. Casein kinase 2 interacting protein 1 (Ckip-1) is a scaffold protein that interacts with various proteins and signals to regulate different cell functions, such as cell morphology, apoptosis, and differentiation. In this study, we verified the suppressive effects of P. gingivalis and lipopolysaccharide (Pg-LPS) on OCCM-30 mineralization. We also showed that Ckip-1 gradually decreased during OCCM-30 mineralization but increased with the aggravation of Pg-induced inflammation. However, it remained unchanged when cells were stimulated with Pg-LPS, regardless of the concentration and incubation time. Then, more cellular cementum and enhanced Osterix expression were observed in Ckip-1 knockout mice when compared with the wild-type mice. Meanwhile, Ckip-1 silencing significantly enhanced cementoblast mineralization with or without P. gingivalis–associated inflammation. The trend was opposite when Ckip-1 was overexpressed. Finally, we found that the p38, Akt, and Wnt pathways were activated, while the Erk1/2 pathway was inhibited when Ckip-1 was silenced. The opposite results were also observed in the Ckip-1 overexpression group. Furthermore, we proved that cell mineralization was weakened when p38, Akt inhibitors were applied and strengthened when the Erk1/2 pathway was inhibited. In summary, Ckip-1 is upregulated under P. gingivalis–induced inflammation and negatively regulates cementoblast mineralization partially through mitogen-activated protein kinases and Akt signaling pathways, which may contribute to the restoration of cementum destroyed by P. gingivalis.

PGC‐1 alpha regulates mitochondrial biogenesis to ameliorate hypoxia‐inhibited cementoblast mineralization

“…It has been previously found that the MAPK pathway contributes to cementum mineralization. [25][26][27] Moreover, the activation of ERK by CoCl 2 -induced hypoxia has been reported in vitro and in vivo, including in OCCM-30 cells. 13,24 Thus, we explored whether the MAPK pathway regulates the mineralization and mitochondria biogenesis of upregulation, including the MAPK, insulin, mTOR, and WNT pathways, which have all been identified as inducers of mitochondrial biogenesis.…”

“…Prior studies have demonstrated that the activation of the p38 mitogen-activated protein kinase (MAPK) pathway enhanced the activity of PGC-1α, 23 and that hypoxia induction led to ERK activation in vitro and in vivo. 13,24 Moreover, it has been proven that the MAPK pathway is essential for cementoblast mineralization; [25][26][27] we, therefore, set out to explore whether the MAPK signaling pathway was involved in this process.…”

M2 macrophages with inflammation tropism facilitate cementoblast mineralization

“…So far, several signaling pathways have been identified as being involved in cementoblast mineralization, such as WNT, 36 Hedgehog, 37 Notch, 38 BMP, 39 TGF-β, 40 Akt, 4,5 MAPKs, 4,5 and other pathways. 41 As an important part of the MAPKs pathway, the p38 signaling was shown to regulate cementoblast mineralization positively, 4,5,41 though activated p38 signaling was also detected in cementoblasts induced with TNF-α, a suppressor of cementoblast mineralization. 42 Strengthened p38 signaling was observed in M2 macrophage-associated groups when compared with their own M0 macrophage-associated controls.…”

Role of NOD2 and hepcidin in inflammatory periapical periodontitis

“…In the oral cavity, activation of NOD2 by muramyl dipeptide (MDP) can upregulate expression of proinflammatory mediators and cytokines, thereby enhancing the immune response of dental pulp to pathogens [ 26 ]. Porphyromonas gingivalis is responsible for destruction of cementum and progression of PP in general [ 27 , 28 ].Upregulation of NOD2 expression may be due to NOD2 activation by MDP in P. gingivalis , which participates in the progression of periapical inflammation. Analyses of functional enrichment of DEGs using the GO database indicated that DEGs were enriched mainly in regulation of the cellular response to lipopolysaccharide (BP), transmembrane receptor protein tyrosine kinase (MF), and intracellular membrane-bounded organelle (CC).…”

“…In the oral cavity, activation of NOD2 by muramyl dipeptide (MDP) can upregulate expression of proinflammatory mediators and cytokines, thereby enhancing the immune response of dental pulp to pathogens [26]. Porphyromonas gingivalisis responsible for destruction of cementum and progression of PP in general [27,28].Upregulation of NOD2 expression may be due to NOD2 activation by MDP in Inflammatory progression is closely related to bone loss. Yuan and colleagues showed thatNOD2-deficiency in rats led to aggravation of inflammatory processes associated with atherosclerosis and periodontitis.…”