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Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis.

ABSTRACT: The potential role of osteoblasts in bone and bone marrow (BM) metastases in neuroblastoma (NBL) remains unclear. In this study, we examined the effect of NBL cells on the osteoblastic differentiation of BM-derived mesenchymal stromal cells (BMMSC). We show that the presence of NBL cells enhanced the osteoblastic differentiation of BMMSC driven by bone morphogenetic protein (BMP)-4, in the absence of any effect on NBL cell proliferation. Expression profiles of BMMSC driven toward osteoblastic differentiation revealed an increase in vascular endothelial growth factor A (Vegfa) expression in the presence of NBL cells. We demonstrated that NBL cells increased BMMSC-derived VEGFA mRNA and protein and that this was enhanced by BMP-4. However, in similar conditions, neither the addition of an mVEGFA blocking antibody nor exogenous recombinant (r) mVEGFA affected osteoblastic differentiation. In contrast, siRNA- mediated knock-down of VEGFA in BMMSC prevented osteoblastic differentiation in BMP-4-treated cocultures, an effect that was not reversed in the presence of rmVEGFA. An analysis of murine bones injected with hNBL cells revealed an increase of mVEGFA producing cells near tumor cells concomitantly with an increase in Vegfa and Runx2 mRNA. This coincided with an increase in osteoclasts, in Rankl/Opg mRNA ratio and with the formation of osteolytic lesions. Thus NBL cells promote osteoblastogenesis in the BM by increasing VEGFA expression in BMMSC. Our study provides a new insight into the role of VEGFA in NBL metastases by pointing to the role of stroma-derived intracrine VEGFA in osteoblastogenesis.

SUBMITTER: HaDuong JH

PROVIDER: S-EPMC5743435 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis.

HaDuong Josephine H JH Blavier Laurence L Baniwal Sanjeev K SK Frenkel Baruch B Malvar Jemily J Punj Vasu V Sposto Richard R DeClerck Yves A YA

International journal of cancer 20150221 4

The potential role of osteoblasts in bone and bone marrow (BM) metastases in neuroblastoma (NBL) remains unclear. In this study, we examined the effect of NBL cells on the osteoblastic differentiation of BM-derived mesenchymal stromal cells (BMMSC). We show that the presence of NBL cells enhanced the osteoblastic differentiation of BMMSC driven by bone morphogenetic protein (BMP)-4, in the absence of any effect on NBL cell proliferation. Expression profiles of BMMSC driven toward osteoblastic di ...[more]

PMID: 25648303

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Project description:BackgroundAging-associated osteoporosis is frequently seen in the elderly in clinic, but efficient managements are limited because of unclear nosogenesis. The current study aims to investigate the role of melatonin on senescent bone marrow stromal cells (BMSCs) and the underlying regulating mechanism.MethodsMelatonin levels were tested by ELISA. Gene expression profiles were performed by RNA-sequencing, enrichment of H3K36me2 on gene promoters was analyzed by Chromatin Immunoprecipitation Sequencing (ChIP-seq), and chromatin accessibility was determined by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq). Osteogenesis of BMSCs in vitro was measured by Alizarin Red and Alkaline Phosphatase staining, and in vivo effects of melatonin was assessed by histological staining and micro computed tomography (micro-CT) scan. Correlation of NSD2 expression and severity of senile osteoporosis patients were analyzed by Pearson correlation.ResultsMelatonin levels were decreased during aging in human bone marrow, accompanied by downregulation of the histone methyltransferase nuclear receptor binding SET domain protein 2 (NSD2) expression in the senescent BMSCs. Melatonin stimulated the expression of NSD2 through MT1/2-mediated signaling pathways, resulting in the rebalancing of H3K36me2 and H3K27me3 modifications to increase chromatin accessibility of the osteogenic genes, runt-related transcription factor 2 (RUNX2) and bone gamma-carboxyglutamate protein (BGLAP). Melatonin promoted osteogenesis of BMSCs in vitro, and alleviates osteoporosis progression in the aging mice. In clinic, severity of senile osteoporosis (SOP) was negatively correlated with melatonin level in bone marrow, as well as NSD2 expression in BMSCs. Similarly, melatonin remarkably enhanced osteogenic differentiation of BMSCs derived from SOP patients in vitro.ConclusionsCollectively, our study dissects previously unreported mechanistic insights into the epigenetic regulating machinery of melatonin in meliorating osteogenic differentiation of senescent BMSC, and provides evidence for application of melatonin in preventing aging-associated bone loss.

Dataset Information

Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis.

Publications

Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis.

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