P2X7 receptors on osteoblasts couple to production of lysophosphatidic acid: a signaling axis promoting osteogenesis

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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.

Section: Expression Of P2x7 In Cells Of the Osteoblast Lineagementioning

confidence: 92%

Section: Expression Of P2x7 In Cells Of the Osteoblast Lineagementioning

confidence: 99%

Expression, signaling, and function of P2X7 receptors in bone

Grol

Panupinthu

Korcok

et al. 2009

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“…Calvarial osteoblasts were isolated from 5-to 7-day-old mice using sequential collagenase digestion, as previously described [12]. Freshly isolated osteoblasts were then plated at 1.0-1.5 × 10 4 cells/cm 2 on Nunc 6-well plates (Thermo Fisher Scientific, Rochester, NY, USA) and maintained in α-MEM supplemented with 10 % FBS and 1 % antibiotic solution (culture medium) at 37°C and 5 % CO 2 .…”

Section: Animals and Cell Culturementioning

confidence: 99%

“…Mice in which P2X7 receptor function is disrupted (knockout) exhibit diminished periosteal bone formation and increased trabecular bone resorption [10] and impaired anabolic responses of the skeleton to mechanical load [11]. In cells of the osteoblast lineage, stimulation of the P2X7 receptor promotes differentiation and matrix mineralization [12]. Additionally, P2X7 is required to initiate signaling following fluid shear stress in cultures of osteoblast-like and osteocyte-like cells [11].…”

Section: Introductionmentioning

confidence: 99%

P2X7 nucleotide receptor signaling potentiates the Wnt/β-catenin pathway in cells of the osteoblast lineage

Grol

Brooks

Pereverzev

et al. 2016

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The P2X7 and Wnt/β-catenin signaling pathways regulate osteoblast differentiation and are critical for the anabolic responses of bone to mechanical loading. However, whether these pathways interact to control osteoblast activity is unknown. The purpose of this study was to investigate the effects of P2X7 activation on Wnt/β-catenin signaling in osteoblasts. Using MC3T3-E1 cells, we found that combined treatment with Wnt3a and the P2X7 agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP) elicited more sustained β-catenin nuclear localization than that induced by Wnt3a alone. Wnt3a-induced increases in β-catenin transcriptional activity were also potentiated by treatment with BzATP. Consistent with involvement of P2X7, a high ATP concentration (1 mM) potentiated Wnt3a-induced β-catenin transcriptional activity, whereas a low concentration (10 μM) of ATP, adenosine 5′-diphosphate (ADP), or uridine 5′-triphosphate (UTP) failed to elicit a response. The potentiation of β-catenin transcriptional activity elicited by BzATP was also inhibited by two distinct P2X7 antagonists: A 438079 and A 740003. Furthermore, responses to Wnt3a in calvarial cells isolated from P2rx7 knockout mice were significantly less than in cells from wild-type controls. In MC3T3-E1 cells, BzATP increased inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), a process that was blocked by A 438079 and diminished by inhibition of protein kinase C. Thus, P2X7 signaling may potentiate the canonical Wnt pathway through GSK3β inhibition. Taken together, we show that P2X7 activation prolongs and potentiates Wnt/β-catenin signaling. Consequently, cross-talk between P2X7 and Wnt/β-catenin pathways may modulate osteoblast activity in response to mechanical loading.

“…Functional studies of P2X7 receptor activation have shown increased [209] and decreased [167] bone formation in response to Bz-ATP. P2X7 receptors mediate blebbing in osteoblasts via a pathway involving lysophosphatidic acid, and it was suggested that this pathway may contribute to P2X7 receptor-stimulated osteogenesis during skeletal development and mechanotransduction [209,210].…”

Section: Functional Effects Of P2 Receptor-mediated Signalling In Ostmentioning

confidence: 99%

Purinergic signalling in the musculoskeletal system

Burnstock

Arnett

Orriss

2013

109

114

It is now widely recognised that extracellular nucleotides, signalling via purinergic receptors, participate in numerous biological processes in most tissues. It has become evident that extracellular nucleotides have significant regulatory effects in the musculoskeletal system. In early development, ATP released from motor nerves along with acetylcholine acts as a cotransmitter in neuromuscular transmission; in mature animals, ATP functions as a neuromodulator. Purinergic receptors expressed by skeletal muscle and satellite cells play important pathophysiological roles in their development or repair. In many cell types, expression of purinergic receptors is often dependent on differentiation. For example, sequential expression of P2X5, P2Y 1 and P2X2 receptors occurs during muscle regeneration in the mdx model of muscular dystrophy. In bone and cartilage cells, the functional effects of purinergic signalling appear to be largely negative. ATP stimulates the formation and activation of osteoclasts, the bone-destroying cells. Another role appears to be as a potent local inhibitor of mineralisation. In osteoblasts, the bone-forming cells, ATP acts via P2 receptors to limit bone mineralisation by inhibiting alkaline phosphatase expression and activity. Extracellular ATP additionally exerts significant effects on mineralisation via its hydrolysis product, pyrophosphate. Evidence now suggests that purinergic signalling is potentially important in several bone and joint disorders including osteoporosis, rheumatoid arthritis and cancers. Strategies for future musculoskeletal therapies might involve modulation of purinergic receptor function or of the ecto-nucleotidases responsible for ATP breakdown or ATP transport inhibitors.