Extracellular calcium increases fibroblast growth factor 2 gene expression via extracellular signal-regulated kinase 1/2 and protein kinase A signaling in mouse dental papilla cells

Kanaya, Sousuke; Binlu, Xiao; Sakisaka, Y.; Suto, Mizuki; Maruyama, Kentaro; Saito, Masahiro; Nemoto, Eiji

doi:10.1590/1678-7757-2017-0231

Cited by 19 publications

(20 citation statements)

References 30 publications

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“…CB2R agonists inhibit cAMP production which has been demonstrated to result in phosphorylation of ERK in the in vitro models 109,111,120‐123 . On the contrary, inverse agonists increase cAMP levels that could activate protein kinase A (PKA) and subsequent phosphorylation of ERK can occur as such is reported in dental pulpal cells 124 and pancreatic β cells 125,126 . The increase in p‐ERK may exert anti‐inflammatory activity via suppression of NF‐κB activation as reported in vascular endothelial cells 127 .…”

Section: Discussionmentioning

confidence: 98%

Cannabinoid type‐2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL‐1β stimulated primary human periodontal ligament fibroblasts

Abidi

Alghamdi

Dabbous

et al. 2020

J of Periodontal Research

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Objective The aim of this study is to understand the role of cannabinoid type 2 receptor (CB2R) during periodontal inflammation and to identify anti‐inflammatory agents for the development of drugs to treat periodontitis (PD). Background Cannabinoid type 2 receptor is found in periodontal tissue at sites of inflammation/infection. Our previous study demonstrated anti‐inflammatory responses in human periodontal ligament fibroblasts (hPDLFs) via CB2R ligands. Methods Anandamide (AEA), HU‐308 (agonist), and SMM‐189 (inverse agonist) were tested for effects on IL‐1β‐stimulated cytokines, chemokines, and angiogenic and vascular markers expressed by hPDLFs using Mesoscale Discovery V‐Plex Kits. Signal transduction pathways (p‐c‐Jun, p‐ERK, p‐p‐38, p‐JNK, p‐CREB, and p‐NF‐kB) were investigated using Cisbio HTRF kits. ACTOne and Tango™ ‐BLA functional assays were used to measure cyclic AMP (cAMP) and β‐arrestin activity. Results IL‐1β stimulated hPDLF production of 18/39 analytes, which were downregulated by the CB2R agonist and the inverse agonist. AEA exhibited pro‐inflammatory and anti‐inflammatory effects. IL‐1β increased phosphoproteins within the first hour except p‐JNK. CB2R ligands attenuated p‐p38 and p‐NFĸB, but a late rise in p‐38 was seen with HU‐308. As p‐ERK levels declined, a significant increase in p‐ERK was observed later in the time course by synthetic CB2R ligands. P‐JNK was significantly affected by SMM‐189 only, while p‐CREB was elevated significantly by CB2R ligands at 180 minutes. HU‐308 affected both cAMP and β‐arrestin pathway. SMM‐189 only stimulated cAMP. Conclusion The findings that CB2R agonist and inverse agonist may potentially regulate inflammation suggest that development of CB2R therapeutics could improve on current treatments for PD and other oral inflammatory pathologies.

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Section: Discussionmentioning

confidence: 98%

Cannabinoid type‐2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL‐1β stimulated primary human periodontal ligament fibroblasts

Abidi

Alghamdi

Dabbous

et al. 2020

J of Periodontal Research

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“…demonstrated that cAMP/PKA and Ras/ERK pathways were linked together and regulated the expressions and phosphorylation of ERK1/2 in melanoma cells . Research on dental papilla cells revealed ERK1/2 and PKA signaling were involved in the regulation of fibroblast growth factor‐2 by extracellular calcium . However, the relationship between PKA and ERK1/2 in cementogenesis has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Intermittent parathyroid hormone promotes cementogenesis in a PKA‐ and ERK1/2‐dependent manner

Zhang

et al. 2019

Journal of Periodontology

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Background: Intermittent parathyroid hormone (PTH) promotes cementogenesis and provides a promising biotherapeutic to rehabilitate resorbed roots. However, the underlying mechanisms remain inconclusive. Cyclic aenosine monophosphate (AMP)-dependent protein kinases A (PKA) and extracellular signal-regulated MAP kinases 1/2 (ERK1/2) are key regulators of bone remodeling. The present study aims to investigate whether PKA and ERK1/2 are involved in the process of intermittent PTH-promoted cementogenesis.Methods: Sprague-Dawley rats in experimental group (n = 30) received a daily subcutaneous injection of PTH and the control (n = 30) received placebo vehicle for 1, 2, 3, 4, and 5 weeks. Results were evaluated by hematoxylin and eosin and immunohistochemistry staining. In vitro, OCCM-30 cells were incubated with intermittent PTH. H89 and U0126 were used to determine the role of PKA and ERK1/2, respectively. The cementogenic results were analyzed by reverse transcription-polymerase chain reaction (RT-PCR), western blotting, alkaline phosphatase activity assay and Alizarin Red S staining. The interaction of PKA and p-ERK1/2 was determined by co-immunoprecipitation (Co-IP). Results:Intermittent PTH exerted anabolic effect on cellular cementum in developing teeth with elevated expression of osteocalcin, osteopontin, and PKA (catalytic subunit) in PTH injection group. The promoting effects of intermittent PTH on cementogenesis and osteogenic differentiation were abrogated by H89 and U0126 in vitro, respectively. Blocking of PKA pathway downregulated intermittent PTH-induced ERK1/2 phosphorylation. Conclusions:Intermittent PTH promotes cementogenesis in a PKA-and ERK1/2dependent manner. In this process, PKA and p-ERK1/2 interact with each other. These results support the future biotherapeutic applications of PTH in cementum resorption.

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“…This bioactive effect has been related to extracellular signal -regulated kinase 2 (ERK1/2) and Mad- related protein 1 (Smad1) pathways, in a mechanism independent of mevalonate, ultimately with bone morphogenetic protein 2 (BMP-2) overexpression, which seems to result in autocrine and paracrine stimulation (Ghosh-Choudhury et al 2007; Chen et al 2010; Karanxha et al 2013; Soares, Anovazzi, et al 2018; Soares, Zhang, et al 2018). The influx of Ca 2+ into cells activated unspecified Ca 2+ channels, which, in turn, led to ERK1/2 phosphorylation along with DSPP, ALP, fibroblast growth factor 2, osteopontin (OPN) and osteocalcin (OCN) overexpression (Woo et al 2013; Li et al 2015; Kanaya et al 2018; Kulan et al 2018). In addition, Smad 1/5/8-BMP-2 activation has also been closely related to the osteogenic differentiation of precursor cells in contact with calcium-releasing sources (Li et al 2015; Kanaya et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Chitosan-Calcium-Simvastatin Scaffold as an Inductive Cell-Free Platform

Soares¹,

Bordini

Bronze‐Uhle³

et al. 2021

J Dent Res

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The development of biomaterials based on the combination of biopolymers with bioactive compounds to develop delivery systems capable of modulating dentin regeneration mediated by resident cells is the goal of current biology-based strategies for regenerative dentistry. In this article, the bioactive potential of a simvastatin (SV)–releasing chitosan-calcium-hydroxide (CH-Ca) scaffold was assessed. After the incorporation of SV into CH-Ca, characterization of the scaffold was performed. Dental pulp cells (DPCs) were seeded onto scaffolds for the assessment of cytocompatibility, and odontoblastic differentiation was evaluated in a microenvironment surrounded by dentin. Thereafter, the cell-free scaffold was adapted to dentin discs positioned in artificial pulp chambers in direct contact with a 3-dimensional (3D) culture of DPCs, and the system was sealed to simulate internal pressure at 20 cm/H2O. In vivo experiments with cell-free scaffolds were performed in rats’ calvaria defects. Fourier-transform infrared spectroscopy spectra proved incorporation of Ca and SV into the scaffold structure. Ca and SV were released upon immersion in a neutral environment. Viable DPCs were able to spread and proliferate on the scaffold over 14 d. Odontoblastic differentiation occurred in the DPC/scaffold constructs in contact with dentin, in which SV supplementation promoted odontoblastic marker overexpression and enhanced mineralized matrix deposition. The chemoattractant potential of the CH-Ca scaffold was improved by SV, with numerous viable and dentin sialoprotein–positive cells from the 3D culture being observed on its surface. Cells at 3D culture featured increased gene expression of odontoblastic markers in contact with the SV-enriched CH-Ca scaffold. CH-Ca-SV led to intense mineralization in vivo, presenting mineralization foci inside its structure. In conclusion, the CH-Ca-SV scaffold induces differentiation of DPCs into a highly mineralizing phenotype in the presence of dentin, creating a microenvironment capable of attracting pulp cells to its surface and inducing the overexpression of odontoblastic markers in a cell-homing strategy.

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Extracellular calcium increases fibroblast growth factor 2 gene expression via extracellular signal-regulated kinase 1/2 and protein kinase A signaling in mouse dental papilla cells

Cited by 19 publications

References 30 publications

Cannabinoid type‐2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL‐1β stimulated primary human periodontal ligament fibroblasts

Cannabinoid type‐2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL‐1β stimulated primary human periodontal ligament fibroblasts

Intermittent parathyroid hormone promotes cementogenesis in a PKA‐ and ERK1/2‐dependent manner

Chitosan-Calcium-Simvastatin Scaffold as an Inductive Cell-Free Platform

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