Activation of the P2Y2 receptor regulates bone cell function by enhancing ATP release

Orriss, Isabel R.; Guneri, Dilek; Hajjawi, Mark; Shaw, Kristy; Patel, Jatin; Arnett, Timothy R.

doi:10.1530/joe-17-0042

Cited by 28 publications

(33 citation statements)

References 58 publications

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“…Deleting the mouse P2Y 2 receptor gene has produced conflicting results. Higher bone mineral content and BMD compared to wild‐type animals was seen by Orriss et al (2017), but Xing et al (2014) reported lower bone volume and strength. Consistent with the latter, overexpression of P2Y 2 receptors in female rats increased femoral length and strength of the femoral neck but had no effect on BMD (Ellegaard et al, 2017).…”

Section: P2y Receptors In the Musculoskeletal Systemmentioning

confidence: 89%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

170

184

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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Section: P2y Receptors In the Musculoskeletal Systemmentioning

confidence: 89%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

170

184

View full text Add to dashboard Cite

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“…These actions are due to both P2 receptor mediated signalling and also direct hydrolysis by NPP1 to produce PP i (Orriss et al, ; Orriss, Key, et al, ; Orriss, Key, Hajjawi, & Arnett, ). Recently, we also demonstrated that activation of the P2Y 2 receptor exerts some of its effects on bone mineralization indirectly by promoting the release of ATP from osteoblasts (Orriss et al, ). In contrast to the potent actions of ATP and UTP, ADP and UDP do not influence bone mineralization (Orriss et al, ).…”

Section: Introductionmentioning

confidence: 95%

Inhibition of arterial medial calcification and bone mineralization by extracellular nucleotides: The same functional effect mediated by different cellular mechanisms

Patel

Zhu

Opdebeeck

et al. 2017

Journal Cellular Physiology

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Arterial medial calcification (AMC) is thought to share some outward similarities to skeletal mineralization and has been associated with the transdifferentiation of vascular smooth muscle cells (VSMCs) to an osteoblast-like phenotype. ATP and UTP have previously been shown to inhibit bone mineralization. This investigation compared the effects of extracellular nucleotides on calcification in VSMCs with those seen in osteoblasts. ATP, UTP and the ubiquitous mineralization inhibitor, pyrophosphate (PPi), dose dependently inhibited VSMC calcification by ≤85%. Culture of VSMCs in calcifying conditions was associated with an increase in apoptosis; treatment with ATP, UTP, and PPi reduced apoptosis to levels seen in non-calcifying cells. Extracellular nucleotides had no effect on osteoblast viability. Basal alkaline phosphatase (TNAP) activity was over 100-fold higher in osteoblasts than VSMCs. ATP and UTP reduced osteoblast TNAP activity (≤50%) but stimulated VSMC TNAP activity (≤88%). The effects of extracellular nucleotides on VSMC calcification, cell viability and TNAP activity were unchanged by deletion or inhibition of the P2Y2 receptor. Conversely, the actions of ATP/UTP on bone mineralization and TNAP activity were attenuated in osteoblasts lacking the P2Y2 receptor. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) hydrolyses ATP and UTP to produce PPi. In both VSMCs and osteoblasts, deletion of NPP1 blunted the inhibitory effects of extracellular nucleotides suggesting involvement of P2 receptor independent pathways. Our results show that although the overall functional effect of extracellular nucleotides on AMC and bone mineralization is similar there are clear differences in the cellular mechanisms mediating these actions.

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“…The effect on bone mineralization is instead controversial. Mechanical forces promote ATP release followed by RUNX2 activation in a human osteoblastic cell line (Costessi et al, 2005) but low concentrations of ATP inhibit mineralization by binding P2Y2 receptor and mice lacking this receptor show an increased bone volume (Orriss et al, 2007;Orriss et al, 2017). Clopidogrel, an inhibitor of platelet aggregation used as a therapy for secondary prevention of the stroke, is an antagonist of P2Y12 receptor and in vitro was able to inhibit murine osteoblast proliferation and viability and to reduce osteoblasts' ability to form bone nodules.…”

Section: P2 Receptorsmentioning

confidence: 99%

Signaling of the Purinergic System in the Joint

Corciulo

Cronstein

2020

Front. Pharmacol.

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The joint is a complex anatomical structure consisting of different tissues, each with a particular feature, playing together to give mobility and stability at the body. All the joints have a similar composition including cartilage for reducing the friction of the movement and protecting the underlying bone, a synovial membrane that produces synovial fluid to lubricate the joint, ligaments to limit joint movement, and tendons for the interaction with muscles. Direct or indirect damage of one or more of the tissues forming the joint is the foundation of different pathological conditions. Many molecular mechanisms are involved in maintaining the joint homeostasis as well as in triggering disease development. The molecular pathway activated by the purinergic system is one of them.The purinergic signaling defines a group of receptors and intermembrane channels activated by adenosine, adenosine diphosphate, adenosine 5'-triphosphate, uridine triphosphate, and uridine diphosphate. It has been largely described as a modulator of many physiological and pathological conditions including rheumatic diseases. Here we will give an overview of the purinergic system in the joint describing its expression and function in the synovium, cartilage, ligament, tendon, and bone with a therapeutic perspective.

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Activation of the P2Y2 receptor regulates bone cell function by enhancing ATP release

Cited by 28 publications

References 58 publications

Update of P2Y receptor pharmacology: IUPHAR Review 27

Update of P2Y receptor pharmacology: IUPHAR Review 27

Inhibition of arterial medial calcification and bone mineralization by extracellular nucleotides: The same functional effect mediated by different cellular mechanisms

Signaling of the Purinergic System in the Joint

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