Endothelin Signaling in Bone

Kristianto, Jasmin; Johnson, Michael G.; Afzal, Rafia; Blank, Robert D.

doi:10.1016/j.ecl.2016.09.014

Cited by 9 publications

(9 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While a similar Edn1-Ednra autocrine effect could be occurring in the Ex6DEL GNP cultures, we did not observe transcriptional activation of Notch signaling components (e.g., Jag1, Hey1) as shown in the Adams et al (2020) study. Despite this difference, endothelin-1 signaling can be transduced through phosphatidylinositol 3-kinase (PI3-K), Wnt, and mitogen-activated protein kinase (MAPK) signaling pathways (Bouallegue et al, 2007;Kristianto et al, 2017), the latter two for which we observed several gene expression differences in the Ex6DEL cultures.…”

Section: Discussionmentioning

confidence: 89%

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Goodwin

Zapata

Timpano

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Chromatin remodeling proteins utilize the energy from ATP hydrolysis to mobilize nucleosomes often creating accessibility for transcription factors within gene regulatory elements. Aberrant chromatin remodeling has diverse effects on neuroprogenitor homeostasis altering progenitor competence, proliferation, survival, or cell fate. Previous work has shown that inactivation of the ISWI genes, Smarca5 (encoding Snf2h) and Smarca1 (encoding Snf2l) have dramatic effects on brain development. Smarca5 conditional knockout mice have reduced progenitor expansion and severe forebrain hypoplasia, with a similar effect on the postnatal growth of the cerebellum. In contrast, Smarca1 mutants exhibited enlarged forebrains with delayed progenitor differentiation and increased neuronal output. Here, we utilized cerebellar granule neuron precursor (GNP) cultures from Smarca1 mutant mice (Ex6DEL) to explore the requirement for Snf2l on progenitor homeostasis. The Ex6DEL GNPs showed delayed differentiation upon plating that was not attributed to changes in the Sonic Hedgehog pathway but was associated with overexpression of numerous positive effectors of proliferation, including targets of Wnt activation. Transcriptome analysis identified increased expression of Fosb and Fosl2 while ATACseq experiments identified a large increase in chromatin accessibility at promoters many enriched for Fos/Jun binding sites. Nonetheless, the elevated proliferation index was transient and the Ex6DEL cultures initiated differentiation with a high concordance in gene expression changes to the wild type cultures. Genes specific to Ex6DEL differentiation were associated with an increased activation of the ERK signaling pathway. Taken together, this data provides the first indication of how Smarca1 mutations alter progenitor cell homeostasis and contribute to changes in brain size.

show abstract

Section: Discussionmentioning

confidence: 89%

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Goodwin

Zapata

Timpano

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Genomic alterations in PLCB4, GNAI3, and EDN1 genes have been identified to be responsible for >90 % of ACS onsets. In this context, it is interesting to note that all these genes have been implicated in endothelin signaling, which plays a critical role as a mediator promoting bone matrix synthesis and mineralization [24][25][26]. It has been reported that conditional knockdown of GATA4 gene causes shorter tooth root and inhibits odonto/osteogenesis.…”

Section: Discussionmentioning

confidence: 99%

Mir24-2-5p suppresses the osteogenic differentiation with Gnai3 inhibition presenting a direct target via inactivating JNK-p38 MAPK signaling axis

Li¹,

Yuan²,

Ni³

et al. 2021

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Background: Congenital anomalies are increasingly becoming a global pediatric health concern, which requires immediate attention to its early diagnosis, preventive strategies, and efficient treatments. Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (Gnai3) gene mutation has been demonstrated to cause congenital small jaw deformity, but the functions of Gnai3 in the disease-specific microRNA (miRNA) upregulations and their downstream signaling pathways during osteogenesis have not yet been reported. Our previous studies found that the expression of Mir24-2-5p was significantly downregulated in the serum of young people with overgrowing mandibular, and bioinformatics analysis suggested possible binding sites of Mir24-2-5p in the Gnai3 3'UTR region. Therefore, this study was designed to investigate the mechanism of Mir24-2-5p-mediated regulation of Gnai3 gene expression and explore the possibility of potential treatment strategies for bone defects. Methods: Synthetic miRNA mimics and inhibitors were transduced into osteoblast precursor cells to regulate Mir24-2-5p expression. Dual-luciferase reporter assay was utilized to identify the direct binding of Gnai3 and its regulator Mir24-2-5p. Gnai3 levels in osteoblast precursor cells were downregulated by shRNA (shGnai3). Agomir, Morpholino Oligo (MO), and mRNA were microinjected into zebrafish embryos to control mir24-2-5p and gnai3 expression. Relevant expression levels were determined by the qRT-PCR and Western blotting. CCK-8 assay, flow cytometry, and transwell migration assays were performed to assess cell proliferation, apoptosis, and migration. ALP, ARS and Von Kossa staining were performed to observe osteogenic differentiation. Alcian blue staining and calcein immersions were performed to evaluate the embryonic development and calcification of zebrafish. Results: The expression of Mir24-2-5p was reduced throughout the mineralization process of osteoblast precursor cells. miRNA inhibitors and mimics were transfected into osteoblast precursor cells. Cell proliferation, migration, osteogenic differentiation, and mineralization processes were measured, which showed a reverse correlation with the expression of Mir24-2-5p. Dual-luciferase reporter gene detection assay confirmed the direct interaction between Mir24-2-5p and Gnai3 mRNA. Moreover, in osteoblast precursor cells treated with Mir24-2-5p inhibitor, the expression of Gnai3 gene was increased, suggesting that Mir24-2-5p negatively targeted Gnai3. Silencing of Gnai3 inhibited osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization. Promoting effects of osteoblast precursor cells proliferation, migration, osteogenic differentiation, and mineralization by low expression of Mir24-2-5p was partially rescued upon silencing of Gnai3. In vivo, mir24-2-5p Agomir microinjection into zebrafish embryo resulted in shorter body length, smaller and retruded mandible, decreased cartilage development, and vertebral calcification, which was partially resc...

show abstract

“…The endothelins mediate their effects through endothelin A (ETA) and endothelin B (ETB) receptors, both expressed by osteoblasts. Endothelin-1 stimulates the proliferation of osteogenic cells; its effects on osteoclasts are still controversial [ 67 ]. ET-1 produced by tumor cells acts in an autocrine manner, enhancing the growth and invasiveness of a tumor, and in a paracrine way on bone cells [ 68 ].…”

Section: Types Of Bone Metastasesmentioning

confidence: 99%

Cellular and Molecular Mediators of Bone Metastatic Lesions

Battafarano

Rossi

Marampon

et al. 2018

IJMS

View full text Add to dashboard Cite

Bone is the preferential site of metastasis for breast and prostate tumor. Cancer cells establish a tight relationship with the host tissue, secreting factors that stimulate or inhibit bone cells, receiving signals generated from the bone remodeling activity, and displaying some features of bone cells. This interplay between tumor and bone cells alters the physiological bone remodeling, leading to the generation of a vicious cycle that promotes bone metastasis growth. To prevent the skeletal-related events (SRE) associated with bone metastasis, approaches to inhibit osteoclast bone resorption are reported. The bisphosphonates and Denosumab are currently used in the treatment of patients affected by bone lesions. They act to prevent or counteract the SRE, including pathologic fractures, spinal cord compression, and pain associated with bone metastasis. However, their primary effects on tumor cells still remain controversial. In this review, a description of the mechanisms leading to the onset of bone metastasis and clinical approaches to treat them are described.

show abstract

Endothelin Signaling in Bone

Cited by 9 publications

References 87 publications

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Mir24-2-5p suppresses the osteogenic differentiation with Gnai3 inhibition presenting a direct target via inactivating JNK-p38 MAPK signaling axis

Cellular and Molecular Mediators of Bone Metastatic Lesions

Contact Info

Product

Resources

About