Adrenomedullin is anti‐apoptotic in osteoblasts through CGRP1 receptors and MEK‐ERK pathway

Uzan, Benjamin; Villemin, Aude; Garel, Jean‐Michel; Cressent, M.

doi:10.1002/jcp.21294

Cited by 37 publications

(49 citation statements)

References 45 publications

(65 reference statements)

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“…The selective inhibitor of MAPK kinase (MEK), PD98059, also eliminates the protective effect of ADM on apoptosis and prevents ADM activation of ERK1/2. These data show that ADM acts as a survival factor in osteoblastic cells via a CGRP1 receptor-MEK-ERK pathway, which provides further understanding on the physiological function of ADM in osteoblasts (47).…”

Section: Discussionmentioning

confidence: 99%

Detection of significant pathways in osteoporosis based on graph clustering

Xiao

Shan

Zhu

et al. 2012

Molecular Medicine Reports

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Abstract. Osteoporosis is the most common and serious skeletal disorder among the elderly, characterized by a low bone mineral density (BMD). Low bone mass in the elderly is highly dependent on their peak bone mass (PBM) as young adults. Circulating monocytes serve as early progenitors of osteoclasts and produce significant molecules for bone metabolism. An improved understanding of the biology and genetics of osteoclast differentiation at the pathway level is likely to be beneficial for the development of novel targeted approaches for osteoporosis. The objective of this study was to explore gene expression profiles comprehensively by grouping individual differentially expressed genes (DEGs) into gene sets and pathways using the graph clustering approach and Gene Ontology (GO) term enrichment analysis. The results indicated that the DEGs between high and low PBM samples were grouped into nine gene sets. The genes in clusters 1 and 8 (including GBP1, STAT1, CXCL10 and EIF2AK2) may be associated with osteoclast differentiation by the immune system response. The genes in clusters 2, 7 and 9 (including SOCS3, SOD2, ATF3, ADM EGR2 and BCL2A1) may be associated with osteoclast differentiation by responses to various stimuli. This study provides a number of candidate genes that warrant further investigation, including DDX60, HERC5, RSAD2, SIGLEC1, CMPK2, MX1, SEPING1, EPSTI1, C9orf72, PHLDA2, PFKFB3, PLEKHG2, ANKRD28, IL1RN and RNF19B.

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Section: Discussionmentioning

confidence: 99%

Detection of significant pathways in osteoporosis based on graph clustering

Xiao

Shan

Zhu

et al. 2012

Molecular Medicine Reports

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“…However, though, cAMP-PKA pathways are coupled to ADM receptors in various types of cells, in osteoblastic cells, changes in cAMP observed by Hamada et al [2002] in the proliferative effect of ADM, had previously been reported to be limited by Grey et al [1999], while for this author, MAPK appeared to be the major pathway mediating the mitogenic effect of ADM. PI3K/Akt signaling has been observed to be activated in some cell types, as in particular, endothelial cells and vascular smooth muscle cells [Iwasaki et al, 2001;Kim et al, 2003], but nothing has been reported about this signaling pathway in osteoblasts. Moreover, as the action of ADM can also be mediated through the CGRP receptor, as has been reported for its mitogenic and anti-apoptotic effects in osteoblasts [Cornish et al, 2003;Uzan et al, 2008], ADM could potentially activate the same signaling pathways as CGRP in osteoblasts. In this sense, it should be noted that it was recently observed [Mrak et al, 2010] that in osteoblasts, CGRP is able to modify the glycogen synthase kinase 3beta (GSK3b) protein and Wnt signaling, which both play an important role in the control of apoptosis [Bodine, 2008].…”

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confidence: 92%

“…ADM has been reported to exert potent bone-stimulatory actions in vivo and to stimulate osteoblast proliferation in vitro [Cornish et al, 1997;Naot et al, 2001;Hamada et al, 2002]. In a previous study, we reported that in addition to its proliferative effect, the action of ADM in osteoblastic cells may also imply the inhibition of apoptosis [Uzan et al, 2008]. It was effectively observed that ADM treatment inhibited apoptosis induced by the withdrawal of growth factors in osteoblastic cells.…”

mentioning

confidence: 94%

“…CGRP was also shown to be anti-apoptotic in these cells. Preliminary investigations of the signaling pathways implicated in the anti-apoptotic effect of ADM allowed to establish a role of the mitogen-activated protein kinase (MAPK), extracellular signal-regulated protein kinase (ERK1/2) signaling pathway, as already reported for its proliferative effect [Cornish et al, 2004], but did not show variations in the apoptotic factors Bax, Bcl-2, bcl-xL [Uzan et al, 2008]. The downstream MAPK signaling transduction cascade that mediates ADM-specific survival signals in osteoblasts therefore remains to be established.…”

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confidence: 98%

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Signal transduction pathways mediating the effect of adrenomedullin on osteoblast survival

Lausson

Cressent

2011

J. Cell. Biochem.

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Adrenomedullin (ADM) plays an important role in the regulation of osteoblastic cells through both a proliferative and an anti-apoptotic effects. The present study investigated mechanisms involved in the effect of ADM on survival. We report that ADM can act in osteoblasts both through a non-transcriptional action, by phosphorylation of different kinases and components, and through a transcriptional effect by activation of CREB. So, we observed by Western blot analysis, modifications in the downstream targets of ERK, the pro-apoptotic protein Bad, which is inactivated by increase in Ser155 phosphorylation, and the transcription factor CREB, which is activated by phosphorylation at Ser133. CREB activation was confirmed by a CRE-dependent gene transcription assay and an immunocytochemical study. This increase in CREB phosphorylation could lead to its enhanced transcriptional activity, as indicated by the induced expression of the proliferation marker, PCNA. Moreover, ADM could also activate the tyrosine kinase Src and the PI3-Kinase, both of which are implicated in survival. The use of specific pharmacological inhibitors allowed to establish that ADM could activate a signaling cascade involving Src, MEK, ERK, p90RSK, and that the effect of ADM, in particular on the CREB protein, greatly depends on the regulatory control of interfering signaling pathways. Moreover, as Wnt signaling plays an important role in the control of osteoblast apoptosis, we explored a major component of this pathway, protein GSK3β. ADM-induced inactivation of GSK3β by phosphorylation at Ser9, highly suggests that ADM could also exert its survival effect in osteoblast via components of the Wnt pathway.

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“…This peptide is released in circulation where it can exert hypotensive effects, acting on vasodilatation and increasing diuresis and Na C secretion in urine (Nishikimi 2007). It has also been shown that AM possesses a local proliferative and antiapoptotic action on several cell types, and is implicated in tumoral neoangiogenesis (Ishikawa et al 2003, Uzan et al 2008. The peptide AM acts through ADMR, RDC1, and calcitonin receptor-like (CRLR) E Thouë nnon, A Pierre et al: Trophic in pheochromocytoma www.endocrinology-journals.org receptors.…”

Section: Introductionmentioning

confidence: 99%

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Thouënnon¹,

Aimar²,

Tanguy³

et al. 2010

Endocrine-Related Cancer

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Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.

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Adrenomedullin is anti‐apoptotic in osteoblasts through CGRP1 receptors and MEK‐ERK pathway

Cited by 37 publications

References 45 publications

Detection of significant pathways in osteoporosis based on graph clustering

Detection of significant pathways in osteoporosis based on graph clustering

Signal transduction pathways mediating the effect of adrenomedullin on osteoblast survival

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

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