P2X7 receptors: role in bone cell formation and function

Abstract

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...

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

“…et al, 2017). The P2X7R is widely expressed in diverse tissues, including hematopoietic cells (Feng et al, 2016), neurons (Miras-Portugal et al, 2017), glia (Stokes et al, 2015;Kaczmarek-Hajek et al, 2018), bone (Agrawal and Gartland, 2015), muscle (Fabbrizio et al, 2019), endothelium (Green et al, 2018), epithelium (Woods et al, 2012), and immune cells (Ferrari et al, 1997). In the exocrine pancreas, P2X7Rs have been shown to be primarily expressed in pancreatic ductal cells where they may contribute to secretory regulation through induction of cation fluxes and interaction with cholinergic signaling (Novak et al, 2010;Burnstock and Novak, 2012).…”

P2X7, a critical regulator and potential target for bone and joint diseases

“…Studies suggested that the Glu496Ala polymorphism of P2X7 receptor is responsible for ATP‐mediated apoptosis in osteoclast (Ohlendorff et al, ). In addition, ATP may cause the disruption of osteoclastic cytoskeleton and the reduction of osteoclasts survival and resorption by initiation of apoptosis (Agrawal & Gartland, ; Miyazaki et al, ). Contradictorily, another study showed that P2X7 antagonists KN‐62 can potently induce the apoptosis of human primary osteoclasts by activating caspase‐3 and inhibiting interleukin‐6 (IL‐6) production (Penolazzi et al, ).…”

Structural insights into the competitive inhibition of the ATP-gated P2X receptor channel

“…The activation of P2X7 receptors stimulates the release of proinflammatory cytokines, such as interleukins and tumor necrosis factor-alpha (TNF-α). Therefore, P2X7 receptors play a crucial role in inflammation, immunity, neurological function, and apoptosis 11, 12 . Accordingly, P2X7 receptors are potential therapeutic candidates for rheumatoid arthritis, hypertension, and atherosclerosis 13, 14 , and clinical trials of chemical compounds targeting P2X7 have been conducted for P2X7-associated diseases 15 .…”