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Periostin promotes migration and osteogenic differentiation of human periodontal ligament mesenchymal stem cells via the Jun amino-terminal kinases (JNK) pathway under inflammatory conditions.

ABSTRACT: OBJECTIVES:Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered to be a promising method for periodontitis treatment. The molecular mechanism of functional regulation by MSCs remains unclear, thus limiting their application. Our previous study discovered that Periostin (POSTN) promoted the migration and osteogenic differentiation of periodontal ligament mesenchymal stem cells (PDLSCs), but it is still unclear whether POSTN is able to restore the regenerative potential of PDLSCs under inflammatory conditions. In this study, we investigated the effect of POSTN on PDLSCs under inflammatory conditions and its mechanism. MATERIALS AND METHODS:PDLSCs were isolated from periodontal ligament tissue. TNF-? was used at 10 ng/mL to mimic inflammatory conditions. Lentivirus POSTN shRNA was used to knock down POSTN. Recombinant human POSTN (rhPOSTN) was used to stimulate PDLSCs. A scratch assay was used to analyse cell migration. Alkaline phosphatase (ALP) activity, Alizarin Red staining and expression of osteogenesis-related genes were used to investigate the osteogenic differentiation potential. Western blot analysis was used to detect the mitogen-activated protein kinases (MAPK) and AKT signalling pathways. RESULTS:After a 10 ng/mL TNF-? treatment, knockdown of POSTN impeded scratch closure, inhibited ALP activity and mineralization in vitro, and decreased expression of RUNX2, OSX, OPN and OCN in PDLSCs, while 75 ng/mL rhPOSTN significantly accelerated scratch closure, enhanced ALP activity and mineralization in vitro, and increased expression of RUNX2, OSX, OPN and OCN. In addition, knockdown of POSTN inhibited expression of phosphorylated c-Jun N-terminal kinase (p-JNK), while 75 ng/mL rhPOSTN increased expression of p-JNK in PDLSCs with TNF-? treatment. Furthermore, inhibition of JNK by its inhibitor SP600125 dramatically blocked POSTN-enhanced scratch closure, ALP activity and mineralization in PDLSCs. CONCLUSIONS:Our results revealed that POSTN might promote the migration and osteogenic differentiation potential of PDLSCs via the JNK pathway, providing insight into the mechanism underlying MSC biology under inflammatory conditions and identifying a potential target for improving periodontal tissue regeneration.

SUBMITTER: Tang Y

PROVIDER: S-EPMC6529146 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Periostin promotes migration and osteogenic differentiation of human periodontal ligament mesenchymal stem cells via the Jun amino-terminal kinases (JNK) pathway under inflammatory conditions.

Tang Yi Y Liu Lin L Wang Pei P Chen Donglei D Wu Ziqiang Z Tang Chunbo C

Cell proliferation 20170823 6

<h4>Objectives</h4>Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered to be a promising method for periodontitis treatment. The molecular mechanism of functional regulation by MSCs remains unclear, thus limiting their application. Our previous study discovered that Periostin (POSTN) promoted the migration and osteogenic differentiation of periodontal ligament mesenchymal stem cells (PDLSCs), but it is still unclear whether POSTN is able to restore the regenerative ...[more]

PMID: 28833827

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Project description:Aberrant biliary hyperproliferation resulting from lack of differentiating signals favoring the maintenance of an immature and proliferative phenotype by biliary epithelial cells are ultimately responsible for ducto/cystogenesis and intrahepatic cholangiocarcinoma (CCA) formation. Mitogen-activated protein kinase (MAPK) signaling is pivotal for CCA-related tumorigenesis. In particular, targeted inhibition of JNK signaling has shown therapeutic potential. However, the cell-type specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remains largely unknown. Here, we aimed to investigate the relevance of JNK function in hepatocytes in experimental carcinogenesis. JNK signaling in hepatocytes was inhibited by crossing AlbCre-JNK1LoxP/LoxP mice with JNK2-deficient mice to generate Jnk1LoxP/LoxP/Jnk2−/− (JNKΔhepa) mice. JNKΔhepa mice were further interbred with hepatocyte-specific Nemo-knockout mice (NEMOΔhepa), a model of chronic liver inflammation and spontaneous hepatocarcinogenesis, to generate NEMO/JNKΔhepa mice. The impact of JNK deletion on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development in NEMOΔhepa mice was determined. Moreover, regulation of essential genes was assessed by RT-PCR, immunoblottings and immunostains. Additionally, JNK2 inhibition, specifically in hepatocytes of NEMOΔhepa/JNK1Δhepa mice, was performed using siRNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of JNK1 and JNK2 in hepatocytes diminished hepatocarcinogenesis in both the DEN model of hepatocarcinogenesis and in NEMOΔhepa mice, but, in contrast, caused massive proliferation of the biliary ducts. Indeed, JNK deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression, but reduced hepatocarcinogenesis. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa livers exhibited overexpression of the IL-6/Stat3 pathway in addition to EGFR-Raf-MEK-ERK cascade. The functional relevance was tested by administering lapatinib - a dual tyrosine kinase inhibitor (TKI) of ErbB2 and EGFR signaling - to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases and effectively blocked EGFR-Raf-MEK-ERK signaling. Our study defines a novel function of JNK in cell fate as well as hepatocarcinogenesis and opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.

Dataset Information

Periostin promotes migration and osteogenic differentiation of human periodontal ligament mesenchymal stem cells via the Jun amino-terminal kinases (JNK) pathway under inflammatory conditions.

Publications

Periostin promotes migration and osteogenic differentiation of human periodontal ligament mesenchymal stem cells via the Jun amino-terminal kinases (JNK) pathway under inflammatory conditions.

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