Prostaglandin D2 induces apoptosis of human osteoclasts by activating the CRTH2 receptor and the intrinsic apoptosis pathway

Li, Yue; Durand, Marianne; Jacob, M. Christian Lebeau; Hogan, Philippe; McManus, Stephen; Roux, Sophie; Brum‐Fernandes, Artur J. de

doi:10.1016/j.bone.2012.06.003

Cited by 16 publications

(15 citation statements)

References 53 publications

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“…PGD2 may regulate neuronal cell death by activating DP receptors or their metabolism, inducing cell apoptosis independently of prostaglandin receptors [41]. Studies have revealed that PGD2 induces apoptosis in human leukemia cells [42] and in human osteoclasts by activating the CRTH2 receptor (PTGDR) [43]. Combined with the finding that siRNA-PTGDR exerts no effect on miR-592-5p expression, our data indicated that miR-592-5p inhibited the PGD2/DP signaling pathway in hippocampal cells suffering from HIBD.…”

Section: Discussionmentioning

confidence: 99%

Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic-Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR

Sun

Guo

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: This study aimed to explore the effect of microRNA-592-5p (miR-592-5p) on hypoxic-ischemic brain damage (HIBD)-induced hippocampal neuronal injury in a neonatal mouse model relative to the involvement of one target gene, PTGDR, and the PGD2/ DP signaling pathway. Methods: A total of 30 neonatal mice aged 7 days were randomly selected to establish an HIBD mouse model. Hippocampal neuronal cells were transfected into a control group, a blank group, a negative control (NC) group, an miR-592-5p mimics group, an miR-592-5p inhibitors group, an siRNA-PTGDR group and an miR-592-5p inhibitors + siRNA-PTGDR group. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analyses were performed to detect the expression levels of miR-592-5p, PTGDR, DP2, Bcl-2 and Bax in tissues and cells. Cell proliferation, cell cycle and apoptosis were detected by MTT assay and flow cytometry, respectively. Results: The expression levels of miR-592-5p and Bcl-2 decreased, while the expression levels of PTGDR, DP2 and Bax increased in the HIBD group. PTGDR is a target gene of miR-592-2p. Compared with the NC and blank groups, the expression levels of PTGDR, DP2 and Bax decreased, while the expression levels of miR-592-5p and Bcl-2 increased in the miR-592-5p mimics group. The siRNA-PTGDR group showed the same trend as that observed in the miR-592-5p mimics group, except with no difference in miR-592-5p expression. The miR-592-5p inhibitors group showed an opposite gene expression trend compared to that in the miR-592-5p mimics group. The S phase of the cell cycle was prolonged, the G1 phase was reduced, proliferation was increased, and the apoptosis rate was decreased in the siRNA-PTGDR and miR-592-5p mimics groups. Opposite trends for cell cycle, proliferation and apoptosis were observed in the miR-592-5p inhibitors group. Conclusions: Our study suggests that miR-592-5p upregulation protects against hippocampal neuronal injury caused by HIBD by targeting PTGDR and inhibiting the PGD2/DP signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic-Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR

Sun

Guo

Zhang

et al. 2018

Cell Physiol Biochem

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“…Among these prostanoids, pro-inflammatory PGE 2 has a predominant role in promoting tumour growth and is assumed to be the most abundant PG found in human bone metabolism and disease [3,4]. PGD 2 can affect bone metabolism by influencing both osteoclast and osteoblast functions, both cells involved in bone remodelling and in vivo fracture repair as well [3,5,6]. In osteoblasts PGD 2 stimulated calcification [7] and altered expression of RANKL and osteoprotegerin [6,8].…”

Section: Introductionmentioning

confidence: 99%

Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death

Koyani

Kitz

Rossmann

et al. 2016

Biochemical Pharmacology

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Despite considerable efforts to improve treatment modalities for osteosarcoma (OS), patient survival remains poor mainly due to pro-survival pathways in OS cells. Among others, prostaglandins (PGs) are the potent regulators of bone homoeostasis and OS pathophysiology. Therefore, the present study aimed to elucidate the impact of 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, a stable PGD2 degradation product) on cell death/cell survival pathways in p53-deficient MG-63 OS cells. Our findings show that 15d-PGJ2 induces generation of reactive oxygen species that promote p38 MAPK activation and subsequent Akt phosphorylation. This pathway induced nuclear expression of Nrf2 and Egr1, and increased transcription of haem oxygenase-1 (HO-1) and the catalytic subunit of glutamate cysteine ligase (GCLc), catalysing the first step in GSH synthesis. Silencing of Nrf2, Egr1 and HO-1 significantly elevated 15d-PGJ2-mediated reduction of cellular metabolic activity. Activation of cell survival genes including HO-1 and GCLc inhibited 15d-PGJ2-induced cleavage of pro-caspase-3 and PARP. Annexin V/propidium iodide staining showed an increase in early/late apoptotic cells in response to 15d-PGJ2. The observed 15d-PGJ2-mediated signalling events are independent of PGD2 receptors (DP1 and DP2) and PPARγ. In addition, the electrophilic carbon atom C9 is a prerequisite for the observed activity of 15d-PGJ2. The present data show that the intracellular redox imbalance acted as a node and triggered both death and survival pathways in response to 15d-PGJ2. Pharmacological or genetic interference of the pro-survival pathway, the p38 MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis, sensitizes MG-63 cells towards 15d-PGJ2-mediated apoptosis.

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“…PGD 2 is a key mediator in vasodilatation [3], bronchoconstriction [4], inhibition of platelet aggregation [5]–[7], artherosclerosis [8], glycogenolysis [9], allergic reaction mediation [10], inflammation [11], [12], and intraocular pressure reduction [13]. It has also been shown to be involved in regulation of sleep [14], body temperature [15], hormone release [16], and bone metabolism [17]–[20]. DP1 is coupled to Gα s and its activation by PGD 2 leads to an increase in intracellular cAMP.…”

Section: Introductionmentioning

confidence: 99%

Inverse Agonist and Pharmacochaperone Properties of MK-0524 on the Prostanoid DP1 Receptor

et al. 2013

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Prostaglandin D2 (PGD2) acts through two G protein-coupled receptors (GPCRs), the prostanoid DP receptor and CRTH2 also known as DP1 and DP2, respectively. Several previously characterized GPCR antagonists are now classified as inverse agonists and a number of GPCR ligands are known to display pharmacochaperone activity towards a given receptor. Here, we demonstrate that a DP1 specific antagonist, MK-0524 (also known as laropiprant), decreased basal levels of intracellular cAMP produced by DP1, a Gαs-coupled receptor, in HEK293 cells. This reduction in cAMP levels was not altered by pertussis toxin treatment, indicating that MK-0524 did not induce coupling of DP1 to Gαi/o proteins and that this ligand is a DP1 inverse agonist. Basal ERK1/2 activation by DP1 was not modulated by MK-0524. Interestingly, treatment of HEK293 cells expressing Flag-tagged DP1 with MK-0524 promoted DP1 cell surface expression time-dependently to reach a maximum increase of 50% compared to control after 24 h. In contrast, PGD2 induced the internalization of 75% of cell surface DP1 after the same time of stimulation. The increase in DP1 cell surface targeting by MK-0524 was inhibited by Brefeldin A, an inhibitor of transport from the endoplasmic reticulum-Golgi to the plasma membrane. Confocal microscopy confirmed that a large population of DP1 remained trapped intracellularly and co-localized with calnexin, an endoplasmic reticulum marker. Redistribution of DP1 from intracellular compartments to the plasma membrane was observed following treatment with MK-0524 for 24 h. Furthermore, MK-0524 promoted the interaction between DP1 and the ANKRD13C protein, which we showed previously to display chaperone-like effects towards the receptor. We thus report that MK-0524 is an inverse agonist and a pharmacochaperone of DP1. Our findings may have important implications during therapeutic treatments with MK-0524 and for the development of new molecules targeting DP1.

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Prostaglandin D2 induces apoptosis of human osteoclasts by activating the CRTH2 receptor and the intrinsic apoptosis pathway

Cited by 16 publications

References 53 publications

Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic-Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR

Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic-Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR

Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death

Inverse Agonist and Pharmacochaperone Properties of MK-0524 on the Prostanoid DP1 Receptor

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