The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro

Agrawal, Ankita; Buckley, Katherine A.; Bowers, Keith; Furber, Mark; Gallagher, James A.; Gartland, Alison

doi:10.1007/s11302-010-9181-z

Cited by 42 publications

(33 citation statements)

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“…The functional consequence of P2X7R expression has also been extensively investigated. Blockade of P2X7R by a monoclonal antibody against the receptor's external domain or specific P2X7R antagonists prevented osteoclast fusion, but not cell clumping, as previously described by our group (Gartland et al 2003a, Agrawal et al 2010. The role of P2X7R in cell fusion is consistent with previous findings in macrophage cell clones, where cells expressing the P2X7R fused spontaneously in vitro whereas the ones lacking P2X7R did not (Di Virgilio et al 1999).…”

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confidence: 90%

P2X7 receptors: role in bone cell formation and function

Agrawal¹,

Gartland²

2015

Journal of Molecular Endocrinology

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The role of the P2X7 receptor (P2X7R) is being explored with intensive interest in the context of normal bone physiology, bone-related diseases and, to an extent, bone cancer. In this review, we cover the current understanding of P2X7R regulation of bone cell formation, function and survival. We will discuss how the P2X7R drives lineage commitment of undifferentiated bone cell progenitors, the vital role of P2X7R activation in bone mineralisation and its relatively unexplored role in osteocyte function. We also review how P2X7R activation is imperative for osteoclast formation and its role in bone resorption via orchestrating osteoclast apoptosis. Variations in the gene for the P2X7R (P2RX7) have implications for P2X7R-mediated processes and we review the relevance of these genetic variations in bone physiology. Finally, we highlight how targeting P2X7R may have therapeutic potential in bone disease and cancer. Purinergic signallingIn the last four decades, extensive investigations have led to the recognition of ATP from a 'molecular unit of energy' to an extracellular messenger molecule. ATP-sensitive purinoceptors, omnipresent in vertebrate tissues, are involved in a wide variety of physiological roles (Burnstock 2013) and their function has also been demonstrated in invertebrates (Verkhratsky & Burnstock 2014). While they traditionally act as cell surface sensors (Khakh & North 2006), their participation in signalling within the intracellular compartment in mammals (Qureshi et al. 2007, Kuehnel et al. 2009, Stokes & Surprenant 2009, Toulme et al. 2010) and even protozoans (Fountain et al. 2007, Ludlow et al. 2009, Sivaramakrishnan & Fountain 2012 has also been recognised.Purines (adenine, guanine and uridine) can act as signalling molecules in the form of their 5 0 -nucleotide triphosphates (such as ATP, GTP and UTP), diphosphates (ADP), monophosphate (AMP) or as a nucleoside (adenosine). They can activate one or more of the 19 receptors which are sorted into three classes: P1 (nucleoside) receptors; the metabotropic P2Y receptors and the ionotropic P2X, both of which are nucleotide triggered. Recently, a new family of purine receptors, AdeR or P0-receptors, responsive to adenine has been cloned from rodents (Bender et al. 2002, Gorzalka et al. 2005, von Kugelgen et al. 2008, Thimm et al. 2013, although the human homologue is yet to be identified. Structural and stoichiometrical evidence suggests that all P2X receptor (P2XR) subunits trimerise to form functional receptors (Nicke et al. 1998, Barrera et al. 2005, Mio et al. 2005, Kaczmarek-Hajek et al. 2012 with the subunits forming either homomultimers or heteromultimers depending on the subtypes (Burnstock 2007). Each unit comprises two transmembrane domains (TM1 and TM2) with an intervening large extracellular loop and cytoplasmic N-and C-termini, and the primary agonist of all homomeric and heteromeric P2XR is ATP. The current view holds that ligand binding causes reduction in the Journal of Molecular EndocrinologyReview A AGRAWAL and A GARTLAND P...

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confidence: 90%

P2X7 receptors: role in bone cell formation and function

Agrawal¹,

Gartland²

2015

Journal of Molecular Endocrinology

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“…P2X7 receptor blockade with selective antagonists or a monoclonal antibody has been shown to inhibit osteoclast formation formation (Agrawal et al, 2010;Gartland et al, 2003a). Analogues of the P2X7 receptor antagonist, KN-62, have also been shown to induce osteoclast apoptosis (Penolazzi et al, 2005).…”

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

confidence: 99%

The role of purinergic signalling in the musculoskeletal system

Orriss

2015

Autonomic Neuroscience

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“…However, a gain of function P2RX7 SNP (rs1718119) was associated with multiple stress fracture occurrence. Functional expression of purinergic receptor P2X7 primarily regulates configuration of osteoclasts (Agrawal et al 2010), as well as augmenting bone formation via a cell-autonomous role that leads to stimulation of mineralisation (Panupinthu et al 2008), which may explain why some P2RX7 polymorphisms have also been associated with low baseline and accelerated bone loss in post-menopausal women (Gartland et al 2012). P2RX7 is a particularly interesting candidate gene in regard to potential gene–physical activity interactions and outcomes for BMD.…”

Section: Genetic Association With Bmdmentioning

confidence: 99%

The interactions of physical activity, exercise and genetics and their associations with bone mineral density: implications for injury risk in elite athletes

et al. 2018

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Low bone mineral density (BMD) is established as a primary predictor of osteoporotic risk and can also have substantial implications for athlete health and injury risk in the elite sporting environment. BMD is a highly multi-factorial phenotype influenced by diet, hormonal characteristics and physical activity. The interrelationships between such factors, and a strong genetic component, suggested to be around 50–85% at various anatomical sites, determine skeletal health throughout life. Genome-wide association studies and case–control designs have revealed many loci associated with variation in BMD. However, a number of the candidate genes identified at these loci have no known associated biological function or have yet to be replicated in subsequent investigations. Furthermore, few investigations have considered gene–environment interactions—in particular, whether specific genes may be sensitive to mechanical loading from physical activity and the outcome of such an interaction for BMD and potential injury risk. Therefore, this review considers the importance of physical activity on BMD, genetic associations with BMD and how subsequent investigation requires consideration of the interaction between these determinants. Future research using well-defined independent cohorts such as elite athletes, who experience much greater mechanical stress than most, to study such phenotypes, can provide a greater understanding of these factors as well as the biological underpinnings of such a physiologically “extreme” population. Subsequently, modification of training, exercise or rehabilitation programmes based on genetic characteristics could have substantial implications in both the sporting and public health domains once the fundamental research has been conducted successfully.

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The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro

Cited by 42 publications

References 37 publications

P2X7 receptors: role in bone cell formation and function

P2X7 receptors: role in bone cell formation and function

The role of purinergic signalling in the musculoskeletal system

The interactions of physical activity, exercise and genetics and their associations with bone mineral density: implications for injury risk in elite athletes

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