Expression, signaling, and function of P2X7 receptors in bone

Grol, Matthew W.; Panupinthu, Nattapon; Korcok, Jasminka; Sims, Stephen M.; Dixon, S. Jeffrey

doi:10.1007/s11302-009-9139-1

Cited by 90 publications

(86 citation statements)

References 97 publications

(160 reference statements)

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“…(60,61) In addition, activation of the P2X7 subtype of ATP receptors promotes bone formation and mineralization. (59,62) Taken together, our data suggest that disruption of adenosine signaling and PP i metabolism in ENT1 -/-mice is associated with disease onset and progression. Although there are no reported associations between mutations in the gene encoding ENT1 in humans and DISH, the high incidence of this disease in the human population argues against an underlying single gene defect.…”

Section: Discussionmentioning

confidence: 55%

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Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Warraich

Bone

Quinonez

et al. 2012

Journal of Bone and Mineral Research

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Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory spondyloarthropathy, characterized by ectopic calcification of spinal tissues. Symptoms include spine pain and stiffness, and in severe cases dysphagia and spinal cord compression. The etiology of DISH is unknown and there are no specific treatments. Recent studies have suggested a role for purine metabolism in the regulation of biomineralization. Equilibrative nucleoside transporter 1 (ENT1) transfers hydrophilic nucleosides, such as adenosine, across the plasma membrane. In mice lacking ENT1, we observed the development of calcified lesions resembling DISH. By 12 months of age, ENT1 -/-mice exhibited signs of spine stiffness, hind limb dysfunction, and paralysis. Micro-computed tomography (mCT) revealed ectopic mineralization of paraspinal tissues in the cervical-thoracic region at 2 months of age, which extended to the lumbar and caudal regions with advancing age. Energy-dispersive X-ray microanalysis of lesions revealed a high content of calcium and phosphorus with a ratio similar to that of cortical bone. At 12 months of age, histological examination of ENT1 -/-mice revealed large, irregular accumulations of eosinophilic material in paraspinal ligaments and entheses, intervertebral discs, and sternocostal articulations. There was no evidence of mineralization in appendicular joints or blood vessels, indicating specificity for the axial skeleton. Plasma adenosine levels were significantly greater in ENT1 -/-mice than in wild-type, consistent with loss of ENT1-a primary adenosine uptake pathway. There was a significant reduction in the expression of Enpp1, Ank, and Alpl in intervertebral discs from ENT1 -/-mice compared to wild-type mice. Elevated plasma levels of inorganic pyrophosphate in ENT1 -/-mice indicated generalized disruption of pyrophosphate homeostasis. This is the first report of a role for ENT1 in regulating the calcification of soft tissues. Moreover, ENT1 -/-mice may be a useful model for investigating pathogenesis and evaluating therapeutics for the prevention of mineralization in DISH and related disorders. ß

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Section: Discussionmentioning

confidence: 55%

“…Adenosine and ATP can regulate cell behavior and gene expression through cell surface receptors-the adenosine receptor family (57) and the P2 family of nucleotide receptors, (58,59) respectively. Adenosine increases intracellular cyclic AMP (cAMP) levels via its A 2A and A 2B receptor subtypes.…”

Section: Discussionmentioning

confidence: 99%

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Warraich

Bone

Quinonez

et al. 2012

Journal of Bone and Mineral Research

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“…The prominent expression of P2X7Rs in lymphocytes, macrophages, and microglia (11)(12)(13)(14) suggests a vital role for this subtype in the immune response (15). P2X7Rs are inactive in healthy tissue because limited release and rapid hydrolysis keep the concentration of extracellular ATP ([ATP] o ) low (Ͻ100 nM) (16 -18).…”

Section: Atp-gated P2x7 Receptors Are Prominently Expressed In Inflammentioning

confidence: 99%

Quantifying Ca2+ Current and Permeability in ATP-gated P2X7 Receptors

Liang¹,

Samways²,

Wolf³

et al. 2015

Journal of Biological Chemistry

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Background: Ca 2ϩ triggers many of the actions of extracellular ATP. Results: We measured the Ca 2ϩ component of the ATP-gated non-selective cation current of P2X7 receptors. Conclusion: Ca 2ϩ flux varied with the species of origin, the splice variant, and the agonist concentration. Significance: Our results suggest that domains that lie outside of the pore regulate the Ca 2ϩ flux of P2X7 receptors.

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“…Moreover, P2X7 signaling can cause the formation of large nonselective membrane pores and induce dynamic membrane blebbing [12,13]. This receptor plays important roles in chronic pain [14,15], apoptosis [16][17][18], bone remodeling [19][20][21], immune responses [22][23][24][25] and the function of exocrine and endocrine organs [26,27].…”

Section: Introductionmentioning

confidence: 99%

Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

Beaucage

Xiao

Pollmann

et al. 2013

Purinergic Signalling

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The P2X7 receptor is an ATP-gated cation channel expressed by a number of cell types. We have shown previously that disruption of P2X7 receptor function results in downregulation of osteogenic markers and upregulation of adipogenic markers in calvarial cell cultures. In the present study, we assessed whether loss of P2X7 receptor function results in changes to adipocyte distribution and lipid accumulation in vivo. Male P2X7 loss-of-function (KO) mice exhibited significantly greater body weight and epididymal fat pad mass than wild-type (WT) mice at 9 months of age. Fat pad adipocytes did not differ in size, consistent with adipocyte hyperplasia rather than hypertrophy. Histological examination revealed ectopic lipid accumulation in the form of adipocytes and/or lipid droplets in several non-adipose tissues of older male KO mice (9-12 months of age). Ectopic lipid was observed in kidney, extraorbital lacrimal gland and pancreas, but not in liver, heart or skeletal muscle. Specifically, lacrimal gland and pancreas from 12-month-old male KO mice had greater numbers of adipocytes in perivascular, periductal and acinar regions. As well, lipid droplets accumulated in the renal tubular epithelium and lacrimal acinar cells. Blood plasma analyses revealed diminished total cholesterol levels in 9-and 12-month-old male KO mice compared with WT controls. Interestingly, no differences were observed in female mice. Moreover, there were no significant differences in food consumption between male KO and WT mice. Taken together, these data establish novel in vivo roles for the P2X7 receptor in regulating adipogenesis and lipid metabolism in an age-and sex-dependent manner.

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Expression, signaling, and function of P2X7 receptors in bone

Cited by 90 publications

References 97 publications

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

Quantifying Ca2+ Current and Permeability in ATP-gated P2X7 Receptors

Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

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