P2 purinergic receptors on osteoblasts and osteoclasts: Potential targets for drug development

Dixon, S. Jeffrey; Sims, Stephen M.

doi:10.1002/(sici)1098-2299(200003)49:3<187::aid-ddr9>3.0.co;2-f

Cited by 70 publications

(52 citation statements)

References 79 publications

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“…On the other hand, disuse suppresses formation and enhances the resorption of bone [10]. The process by which mechanical stimuli are translated into cellular responses, known as mechanotransduction, has been suggested to involve nucleotide release and subsequent P2 receptor activation [10,18].…”

Section: Regulation Of Bone Remodelingmentioning

confidence: 99%

“…These receptors are subdivided into two classes: the P2Y family of G protein-coupled receptors and the P2X family of ligand-gated cation channels [19]. Nucleotides released in response to mechanical stimulation or inflammation may serve as autocrine/paracrine regulators of both osteoblast and osteoclast function (reviewed in [18,[20][21][22][23]). Thus, nucleotides and the complex network of P2 receptors in bone may underlie the well-recognized responses of skeletal tissues to mechanical stimulation.…”

Section: P2x7 In Bonementioning

confidence: 99%

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Expression, signaling, and function of P2X7 receptors in bone

Grol

Panupinthu

Korcok

et al. 2009

Purinergic Signalling

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Nucleotides released from cells in response to mechanical stimulation or injury may serve as paracrine regulators of bone cell function. Extracellular nucleotides bind to multiple subtypes of P2 receptors on osteoblasts (the cells responsible for bone formation) and osteoclasts (cells with the unique ability to resorb mineralized tissues). Both cell lineages express the P2X7 receptor subtype. The skeletal phenotype of mice with targeted disruption of P2rx7 points to interesting roles for this receptor in the regulation of bone formation and resorption, as well as the response of the skeleton to mechanical stimulation. This paper reviews recent work on the expression of P2X7 receptors in bone, their associated signal transduction mechanisms and roles in regulating bone formation and resorption. Areas for future research in this field are also discussed.

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Section: Regulation Of Bone Remodelingmentioning

confidence: 99%

Section: P2x7 In Bonementioning

confidence: 99%

Expression, signaling, and function of P2X7 receptors in bone

Grol

Panupinthu

Korcok

et al. 2009

Purinergic Signalling

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“…Many ligands such as PTH, endothelin, and nucleotides bind to G q -coupled receptors to induce release of calcium from intracellular stores and activate protein kinase C, which in turn contribute to the regulation of genes such as insulin-like growth factor-binding protein 5 (47) and transforming growth factor ␤1 in osteoblastic cells (48). Nucleotides act through G q -coupled P2Y receptors on osteoblasts to stimulate proliferation (32). Recently, Pasteurella multocida toxin, which activates G q , has been shown to inhibit osteoblast differentiation (49).…”

Section: Discussionmentioning

confidence: 99%

“…2A) (n ϭ 5, p Ͼ 0.2). ATP binds to and activates both P2X and P2Y nucleotide receptors in osteoblasts (32). Activated P2Y receptors couple to G q to increase cytosolic calcium, whereas P2X receptors are ligand-gated cation channels.…”

Section: Figure 1 Regulation Of Rgs2 Protein Expression In Osteoblastsmentioning

confidence: 99%

“…Unlike ATP, UTP activates a subset of P2Y receptors but is not an agonist at any P2X receptor. Thus, we can be confident that responses to UTP are mediated exclusively by G q activation of PLC-␤ (32,33). Similar to ATP, there was no significant difference in the UTP-stimulated peak calcium increase between osteoblasts isolated from wild type and rgs2 Ϫ/Ϫ mice (Fig.…”

Section: Figure 1 Regulation Of Rgs2 Protein Expression In Osteoblastsmentioning

confidence: 99%

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Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

Roy

Nunn

Hong

et al. 2006

Journal of Biological Chemistry

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Regulator of G protein signaling (RGS) proteins limitG protein-coupled receptors (GPCRs) 6 respond to a variety of hormones, paracrine factors, and neurotransmitters by activating heterotrimeric G proteins. Upon activation of the G protein, G␣ is stimulated to exchange bound GDP for cytosolic GTP and is thought to subsequently dissociate from the ␤␥ dimer. Both G␣ and the ␤␥ dimer are then capable of interacting with cellular effectors for a period of time that is limited by the intrinsic GTPase activity of the G␣ subunit. Regulator of G protein signaling (RGS) proteins can reduce the duration of these interactions by increasing the rate of GTP hydrolysis by the G␣ subunits, or by otherwise blocking interactions between G␣ and its target enzymes through a poorly understood process sometimes referred to as "effector antagonism" (1, 2).G protein signaling in osteoblasts is a critical regulator of bone formation. The predominant GPCRs expressed by osteoblasts include the parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor type 1 (PTH1R), P2Y nucleotide receptors, and prostaglandin receptors (3). Other GPCRs found in osteoblasts include endothelin, adenosine, ␤-adrenergic, angiotensin II, and calcium-sensing receptors (3, 4). Binding of PTH to its specific receptor, PTH1R, predominantly leads to the activation of G s (although under certain conditions the receptor can also couple to G q and G i ) (5, 6). Activated G s stimulates adenylyl cyclase to generate intracellular cAMP, which results in the activation of protein kinase A. Stimulation of G q promotes the activity of phospholipase C-␤ (PLC-␤), resulting in the accumulation of inositol 1,4,5-trisphosphate and diacylglycerol, which lead, respectively, to release of calcium from intracellular stores and activation of protein kinase C. Nucleotide stimulation of P2Y receptors in osteoblasts results in PLC-␤ activation and calcium mobilization, with no effect on adenylyl cyclase (3, 7).

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2009

Biophysical Bone Behavior

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P2 purinergic receptors on osteoblasts and osteoclasts: Potential targets for drug development

Cited by 70 publications

References 79 publications

Expression, signaling, and function of P2X7 receptors in bone

Expression, signaling, and function of P2X7 receptors in bone

Up-regulation of Endogenous RGS2 Mediates Cross-desensitization between Gs and Gq Signaling in Osteoblasts

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