Chemerin/ChemR23 regulates cementoblast function and tooth resorption in mice via inflammatory factors

Abstract

Background Periodontitis and orthodontic treatment can lead to inflammatory root resorption (IRR) through an unclear mechanism. Chemerin, a novel chemoattractant protein, is closely associated with inflammation, affects osteoblast and osteoclast differentiation, and may play a role in IRR. We aimed to explore possible roles of the chemerin/ChemR23 interaction in cementoblast function and IRR and reveal a new IRR therapeutic target. Methods Cementoblast function‐related gene and protein expression in the immortalized murine cementoblast cell line OCCM‐30 after treatment with chemerin and siChemR23 was examined by qRT‐PCR and Western blotting. The roles of the MAPK and PI3K‐Akt signaling pathways were studied using specific inhibitors. Cementoblast cytokine production under different treatment conditions was measured by enzyme‐linked immunosorbent assay and qRT‐PCR. Additionally, we modeled IRR in wild‐type and chemerin‐overexpressing mice and injected transgenic mice with anti‐ChemR23 antibody to block ChemR23. We then calculated the root resorption volume and examined periodontal tissue cathepsin K, Runx2, tumor necrosis factor‐α (TNF‐α), and interleukin‐6 (IL‐6) expression. Result Chemerin suppressed cementoblast differentiation and mineralization and exerted a proinflammatory effect on cementoblasts. These effects were partially reversed by siChemR23 and reversed to different extents by p38, Erk1/2 and PI3K‐Akt pathway inhibition, suggesting p38, Erk1/2 and PI3K‐Akt pathways as signaling pathways downstream of chemerin/ChemR23. In vivo, chemerin overexpression worsened IRR. Moreover, chemerin expression was positively correlated with TNF‐α, IL‐6, and cathepsin K expression and negatively correlated with Runx2 expression. ChemR23 downregulation reversed these effects. Conclusion Chemerin/ChemR23 induced TNF‐α and IL‐6 expression dependent on Erk1/2, p38 MAPK, and PI3K‐Akt signaling pathway activation, thereby regulating cementoblast function and affecting IRR.

Macrophages with Different Polarization Phenotypes Influence Cementoblast Mineralization through Exosomes

“…The markers of macrophages have also been shown to diversely affect cementoblast mineralization. The M1 polarization markers IL-1β, IL-6, and TNF-α were observed to attenuate the mineralization of cementoblasts, while the M2 polarization marker PPARγ was suggested to be a promoter of cementoblast mineralization [14][15][16][17]. In the present study, we examined the effect of macrophages with different polar-ization phenotypes on the mineralization of cementoblasts.…”

“…On that basis, Li et al conducted in vitro experiments to demonstrate that M2-polarized macrophages could enhance the cementoblastic differentiation of periodontal ligament stem cells [13]. Further explorative experiments found that the M1 polarization markers IL-1β, IL-6, and TNF-α could attenuate the mineralization of cementoblasts, while the M2 polarization marker PPARγ promoted cementoblast mineralization [14][15][16][17]. These results all suggested a potential linkage between macrophages, cementoblasts, and root resorption.…”

Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner

“…Previous studies showed that chemerin is positively correlated with TNF-α expression [ 29 , 30 ], a known potent pro-mesenchymal factor in GBM [ 24 , 26 ]. Thus, we subsequently investigated whether this chemerin-mediated pro-mesenchymal effect in GBM cells was dependent on TNF-α.…”

Chemerin contributes to inflammatory responses and suppresses osteogenic differentiation in chronic periodontitis

“…Although previous study indicated that chemerin accelerated bone formation and osteogenic differentiation via Akt/Gsk3β/β‐catenin axis in bone marrow (Li et al, 2021), which was opposite of our observations. Considering that chemerin was also reported to inhibit the osteogenic differentiation of cementoblasts in mice (Ye et al, 2020), these opposite role of chemerin on osteogenic differentiation might be caused by the different origin of chemerin, which suggested that chemerin in different locations might have diversity functions. This might need further exploration.…”

“…However, its underlying mechanism of chemerin during chronic periodontitis remains unknown. Moreover, chemerin was also reported to inhibit the osteogenic differentiation of cementoblasts in mice (Ye et al, 2020). Therefore, our current study aimed to uncover the underlying mechanism of chemerin in the chronic periodontitis.…”