ADAM gene expression and regulation during human osteoclast formation

Verrier, Sophie; Hogan, Aileen; McKie, Norman; Horton, Michael A.

doi:10.1016/j.bone.2003.12.029

Cited by 62 publications

(43 citation statements)

References 48 publications

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“…22 Though ADAM12's localization to the syncytium suggests that it may play a role in directing trophoblast differentiation into multinucleated structures, the importance of ADAM12 in synCT formation has not yet been tested. Functional studies in mice identify ADAM12 as a regulator in myogenesis via effects on cell fusion, 23,24 and consistent with this, ADAM12S has been shown to direct osteoclast fusion in bone; 25 however, the molecular mechanism(s) central to these ADAM12-directed processes are poorly understood. In this study, we examine the importance of ADAM12 in regulating trophoblast fusion.…”

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confidence: 78%

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

et al. 2015

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Trophoblasts, placental cells of epithelial lineage, undergo extensive differentiation to form the cellular components of the placenta. Trophoblast progenitor cell differentiation into the multinucleated syncytiotrophoblast is a key developmental process required for placental function, where defects in syncytiotrophoblast formation and turnover associate with placental pathologies and link to poor pregnancy outcomes. The cellular and molecular processes governing syncytiotrophoblast formation are poorly understood, but require the activation of pathways that direct cell fusion. The protease, A Disintegrin and Metalloproteinase 12 (ADAM12), controls cell fusion in myoblasts and is highly expressed in the placenta localizing to multiple trophoblast populations. However, the importance of ADAM12 in regulating trophoblast fusion is unknown. Here, we describe a function for ADAM12 in regulating trophoblast fusion. Using two distinct trophoblast models of cell fusion, we show that ADAM12 is dynamically upregulated and is under the transcriptional control of protein kinase A. siRNA-directed loss of ADAM12 impedes spontaneous fusion of primary cytotrophoblasts, whereas overexpression of the secreted variant, ADAM12S, potentiates cell fusion in the Bewo trophoblast cell line. Mechanistically, both ectopic and endogenous levels of ADAM12 were shown to control trophoblast fusion through E-cadherin ectodomain shedding and remodeling of intercellular boundaries. This study describes a novel role for ADAM12 in placental development, specifically highlighting its importance in controlling the differentiation of villous cytotrophoblasts into multinucleated cellular structures. Moreover, this work identifies E-cadherin as a novel ADAM12 substrate, and highlights the significance that cell adhesion molecule ectodomain shedding has in normal development. Cell Death and Differentiation (2015) 22, 1970-1984 doi:10.1038/cdd.2015 published online 24 April 2015 In mammalian development, the placenta forms the mechanical and physiological link between maternal and fetal circulations. In rodents and higher order primates, including humans, this transfer is achieved through extensive uterine infiltration by fetal-derived cells of epithelial lineage called trophoblasts.1 Trophoblast differentiation is essential for optimal placental function, where the underlying molecular processes regulating specific functions of distinct trophoblast populations are strictly controlled. Defects in trophoblast differentiation associate with impaired placental function and directly impact fetal and maternal health. Within the placenta, progenitor trophoblasts (also called villous cytotrophoblasts; vCTs) overlie a well-defined basal lamina forming an organized, mitotically active epithelial layer. vCT differentiation into an overlying multinucleated structure called the syncytiotrophoblast (synCT) is a key event in placental development. 3 The synCT, composed of millions of nuclei sharing one common cytoplasm, directs nutrient and gas exchange between m...

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confidence: 78%

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

et al. 2015

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“…Primers to ADAM10 [12] were obtained from GeneWorks (Hindmarsh, Australia). PCR amplification was performed using the MyTaq One-Step RT-PCR Kit (Bioline, Sydney, Australia) according to the manufacturer's instructions.…”

Section: Detection Of Adam10 By Rt-pcrmentioning

confidence: 99%

Human P2X7 receptor activation induces the rapid shedding of CXCL16

Pupovac

Foster

Sluyter

2013

Biochemical and Biophysical Research Communications

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Activation of the purinergic P2X7 receptor by extracellular ATP induces the shedding of cell-surface molecules including the low-affinity IgE receptor, CD23 from leukocytes. CD23 is a known substrate of a disintegrin and metalloprotease (ADAM)10. The aim of the current study was to determine if P2X7 activation induced the shedding of the chemokine CXCL16, an ADAM10 substrate. Using immunolabelling and flow cytometry we demonstrate that human RPMI 8226 multiple myeloma B cells, which have been previously shown to express P2X7, also express CXCL16. Flow cytometric and ELISA measurements of ATP-induced loss of cell-surface CXCL16 showed that ATP treatment of RPMI 8226 cells induced the rapid shedding of CXCL16. Treatment of RPMI 8226 cells with the specific P2X7 antagonists, AZ10606120 and KN-62 impaired ATP-induced CXCL16 shedding by ∼86% and ∼90% respectively. RT-PCR demonstrated that ADAM10 is expressed in these cells and treatment of cells with the ADAM10 inhibitor, GI254023X, impaired ATP-induced CXCL16 shedding by ∼87%. GI254023X also impaired P2X7-induced CD23 shedding by ∼57%. This data indicates that human P2X7 activation induces the rapid shedding of CXCL16 and that this process involves ADAM10.

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“…Cells in the osteoclast lineage express ADAM10 and other ADAMs during differentiation (data not shown) (23,24). To determine whether MMPs cleave ephrinA2 on osteoclasts, we used fluorescence-activated cell sorter to analyze cell surface ephrinA2 in the presence or absence of BB94, a widely used inhibitor of MMPs and ADAMs.…”

Section: Expression Of Ephrina2 and Epha2 In Osteoclast Andmentioning

confidence: 99%

Bidirectional Signaling through EphrinA2-EphA2 Enhances Osteoclastogenesis and Suppresses Osteoblastogenesis

Irie¹,

Takada²,

Watanabe³

et al. 2009

Journal of Biological Chemistry

151

166

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Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cellcell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals into respective cells and presumably facilitates transition from bone resorption to bone formation. Here we show that bidirectional ephrinA2-EphA2 signaling regulates bone remodeling at the initiation phase. EphrinA2 expression was rapidly induced by receptor activator of NF-B ligand in osteoclast precursors; this was dependent on the transcription factor c-Fos but independent of the c-Fos target gene product NFATc1. Receptor EphA2 was expressed in osteoclast precursors and osteoblasts. Overexpression experiments revealed that both ephrinA2 and EphA2 in osteoclast precursors enhanced differentiation of multinucleated osteoclasts and that phospholipase C␥2 may mediate ephrinA2 reverse signaling. Moreover, ephrinA2 on osteoclasts was cleaved by metalloproteinases, and ephrinA2 released in the culture medium enhanced osteoclastogenesis. Interestingly, differentiation of osteoblasts lacking EphA2 was enhanced along with alkaline phosphatase, Runx2, and Osterix expression, indicating that EphA2 on osteoblasts generates anti-osteoblastogenic signals presumably by up-regulating RhoA activity. Therefore, ephrinA2-EphA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation.Bone remodeling maintains bone mass constant during adulthood (1, 2). Resorption of old mineralized bone by osteoclasts is followed by new bone formation by osteoblasts. These processes, consisting of the initiation, transition, and termination phases, are tightly regulated by communication between osteoclasts and osteoblasts (3). Bone resorption is excessive in the most common skeletal diseases such as osteoporosis, but molecular mechanisms that balance bone remodeling are only partially understood.Osteoclasts are multinucleated cells (MNCs) 3 responsible for bone resorption. They originate from the fusion of hematopoietic precursor cells of the monocyte/macrophage lineage. Osteoblasts express the two major membrane-bound proteins required for osteoclast differentiation, macrophage-colony stimulating factor (M-CSF), and the receptor activator of NF-B ligand (RANKL). Soluble forms of M-CSF and RANKL allow us to generate osteoclasts from M-CSF-dependent macrophages (MDMs) in cultures. Downstream signaling pathways ultimately activate critical osteoclastogenic transcription factors such as c-Fos (4) and NFATc1 (5-7). NFATc1 is a target gene product of c-Fos (8) and activates gene expression of tartrate-resistant acid phosphatase (TRAP), calcitonin receptor, and ephrinB2.Ephrin ligands and Ep...

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ADAM gene expression and regulation during human osteoclast formation

Cited by 62 publications

References 48 publications

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion

Human P2X7 receptor activation induces the rapid shedding of CXCL16

Bidirectional Signaling through EphrinA2-EphA2 Enhances Osteoclastogenesis and Suppresses Osteoblastogenesis

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