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ThrSer SNP or the gain-of-function c. Both the c. ArgGln and c.

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Again, the authors acknowledged that further clarification and replication in a larger cohort was warranted to confirm their findings. Clearly, further replication of the above observations in RA and aseptic loosening are warranted. As are further analysis of large cohorts such as DOPS and APOSS for SNPs in other purinergic receptors such as the P2Y 2 receptor, which has a role in bone homeostasis and is also known to have numerous functional polymorphisms associated with other human diseases Wesselius et al.

As stated earlier, purinergic signaling is the most primitive and ubiquitous cell-to-cell signaling system that exists, and one might worry that any drug developed specifically to target one particular receptor for one particular disease may have effects in other systems.

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The P2Y 12 receptor is known to play an important role in platelet activation — and P2Y 12 antagonists have proven therapeutic value in the treatment and prevention of coronary artery disease. As mentioned earlier, the P2Y 12 receptor has previously been identified as being expressed on human osteoblasts Buckley et al. Taking these previous reports into consideration, Vestergaard et al.

In this study, they found that the inhibitors dipyridamole and acetylsalicylic acid were associated with increased fracture, whereas clopidogrel was not. Even though this was a large scale study where all patients sustaining a fracture during the year of from the Danish population were included approximately , cases from 5. Given that the number of defined daily doses DDD of clopidogrel sold increased by a factor of 30 from , in to 3.

What is behind these associations has yet to be elucidated. It could be as a consequence of low-grade inflammation associated with atherosclerosis: inflammation is often accompanied by bone loss and subsequently osteoporosis, thus the inflammation related to cardiovascular disease could be a contributing factor to the bone loss in the clopidogrel-treated group. Direct antagonism of P2Y 12 receptor expressed by both osteoblasts and osteoclasts could also be a contributing factor.

Antagonism of the P2Y 12 receptor on both cell types would disrupt the balance of bone homeostasis modulating both bone formation and resorption. This has recently been confirmed by Syberg et al. One might speculate that the in vitro observations were due to a non-specific effect of clopidogrel, which is a pro-drug that is rapidly metabolized in the liver to form the active metabolite; whether this occurs in these cultures is undetermined.

The authors address this in their manuscript by providing supporting in vitro evidence for a direct effect in the form of alterations in cAMP levels and mRNA for key osteoblastic genes in osteoblasts following clopidogrel treatment. However, they acknowledge that off target, non-P2Y 12 receptor-mediated effects on osteoblasts in vitro cannot be fully discounted. They then provide further in vivo evidence that clopidogrel has a detrimental effect on bone by comparing the bone parameters of ovariectomized mice with ovariectomized mice treated daily for 4 weeks with clopidogrel.

Clopidogrel-treated mice had exaggerated effects of ovariectomy including significantly increased bone resorption and decreased bone formation markers, as well as enhanced bone loss as evidenced by significantly larger reductions in BMD, trabecular bone volume, and trabecular number. Clearly, further studies into the exact mechanism of action of clopidogrel, and the newer and more potent anti-platelet drugs such as prasugrel and ticagrelor, on bone metabolism are both timely and necessary.

Bone Remodeling and Modeling

Finally, the role of purinergic signaling in cancer is gradually emerging Deli and Csernoch, , but the role of ATP and P2 receptors in bone cancer and cancer-induced bone disease CIBD still relatively unexplored. The P2X7 receptor has been implicated in many cancer types and its antagonism proposed as a potential treatment Roger and Pelegrin, Given its role in bone cells one would speculate that it would be involved in bone cancer or CIBD.

To date, only one study has investigated purinergic signaling in bone cancer, specifically the P2X7 receptor in bone cancer pain. In this study, Hansen et al.

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They demonstrated that P2X7R-deficient mice were still susceptible to bone cancer pain and compared to cancer-bearing WT mice had an earlier onset of pain-related behaviors. There was no apparent difference in the bone destruction or tumor burden between WT and P2X7R-deficient mice, although the authors note that due to the advanced stage of cancer there was not a reliable measure of tumor burden in their model. They suggest that differences between the two genotypes could not be ruled out and experiments exploring earlier time points to fully elucidate the role of the P2X7 receptor in bone cancer are warranted.

Clearly, we have come a long way in purinergic signaling in bone since the first description almost 20 years ago and we have made significant advances in the past few years thanks to some great collaboration. The availability of more KO and transgenic models as well as the development and use of specific antagonists for other conditions will undoubtedly help us to elucidate further the exact roles purinergic signaling pathways have to play in bone homeostasis, both in health and disease.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Endocrinol Lausanne v. Front Endocrinol Lausanne. Published online Sep Robin M. Author information Article notes Copyright and License information Disclaimer. Received Apr 29; Accepted Sep 4. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

This article has been cited by other articles in PMC. Abstract Purinergic signaling in bone was first proposed in the early s with the observation that extracellular ATP could modulate events crucial to the normal functioning of bone cells. Open in a separate window. SUMMARY Clearly, we have come a long way in purinergic signaling in bone since the first description almost 20 years ago and we have made significant advances in the past few years thanks to some great collaboration. Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The effects of P2X7 receptor antagonists on the formation and function of human osteoclasts in vitro. Purinergic Signal. Age-dependent changes in osteoclast formation in a new strain of P2X7 receptor knockout mice. P2X7 receptor gene polymorphism analysis in rheumatoid arthritis. Favus M. Transcriptional activity of nuclei in multinucleated osteoclasts and its modulation by calcitonin.

Extracellular nucleotide signaling: a mechanism for integrating local and systemic responses in the activation of bone remodeling. Release and interconversion of P2 receptor agonists by human osteoblast-like cells. Evolution of P2X receptors. Wiley Interdiscip. Purinergic signaling. Editorial: molecular endocrinology articles in the spotlight for January Mechanical strain and bone cell function: a review.

The purinergic P2Z receptor of human macrophage cells. Characterization and possible physiological role. The ADP receptor P2Y12 is expressed in developing osteoclasts and is required for full osteoclast function and tumor associated osteolysis. Cancer Treatment Rev. Blockade of the pore-forming P2X7 receptor inhibits formation of multinucleated human osteoclasts in vitro.

Tissue Int. P2X7 receptor-deficient mice maintain the ability to form multinucleated osteoclasts in vivo. Gene Expr. P2X receptors in bone. Purinergic signalling in osteoblasts. Polymorphisms in the P2X7 receptor gene are associated with low lumbar spine bone mineral density and accelerated bone loss in post-menopausal women. Expression, signaling, and function of P2X7 receptors in bone. The bone phenotype of the adult P2Y6R knockout mouse. P2X7 receptor-deficient mice are susceptible to bone cancer pain.

Extracellular ADP is a powerful osteolytic agent: evidence for signaling through the P2Y 1 receptor on bone cells. Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures. Clopidogrel and the risk of osteoporotic fractures: a nationwide cohort study. Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption. Mechanobiology of bone tissue.

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Purinergic regulation of cytosolic calcium and phosphoinositide metabolism in rat osteoblast-like osteosarcoma cells. As osteoblasts are responsible for bone formation organic matrix, primarily composed of type I collagen with and eventual deposition of hydroxyapatite mineral , they are essential for the maintenance of bone mass.

P2X7R expression has been consistently reported in human and rodent cells of osteoblast lineage osteoblast-like cell lines, calvarial and bone-derived primary osteoblasts by RT-PCR, immunochemistry and cell permeabilisation experiments Nakamura et al. It is noteworthy that only a subpopulation of bone-derived and calvarial osteoblasts demonstrate a positive nucleotide response Gartland et al. In addition, blockade or absence of P2X7R has been shown to inhibit propagation of intercellular calcium signalling between osteoblasts and osteoclasts in human bone marrow-derived cells Jorgensen et al.

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It is evident that functional P2X7R is required during osteogenesis Fig. While rat calvariae-derived osteoblasts show inhibited mineralisation in the presence of P2X7R agonists Orriss et al. The differences between culture methodologies in the two studies could in part explain the discrepancies in these studies. Orriss et al. Panupinthu et al. LPA signalling involves Rho-associated kinase, which has established roles in driving non-committed cells towards osteoblast lineage McBeath et al.

Therefore, it is likely that the observations of Panupinthu et al. Furthermore, the significance of these observations is confirmed in humans as several polymorphisms in the P2RX7 imparting reduced function to the P2X7R are associated with increased osteoporosis risk in different human cohorts Ohlendorff et al. Hydrolysis of extracellular ATP generates ATP derivatives and pyrophosphate PPi , both of which contribute negatively to osteoblast function while extracellular ATP basal or mechanical stimuli induced has an osteogenic effect. Agonist mediated transient P2X7R activation promotes osteoblast differentiation and matrix mineralisation; however, sustained stimulus is anti-osteogenic caused by accumulation of extracellular ATP evoking apoptosis.

During the process of bone formation, some osteoblasts become incorporated within the mineralised matrix as osteocytes.

Regulation and signaling of Rho GTPases

There is evidence of functional P2X7R in these matrix embedded cells, but involvement of P2X7R activation in downstream signalling in osteocytes is unclear. Citation: Journal of Molecular Endocrinology 54, 2; Other effects of P2X7R activation on osteoblast function include phospholipase D and A 2 stimulation Panupinthu et al. In this context, it has been shown that while short-term application of BzATP induces reversible membrane blebbing without activating the key apoptotic mediator caspase-3 in murine osteoblastic cells Li et al. Table 1 summarises the effect of P2X7R expression on osteoblasts.

Table 1 Effects of P2X7 receptor on bone cells. Osteocytes are terminally differentiated osteoblast cells which become incorporated within the mineralised matrix in the process of bone formation. Their slender cytoplasmic processes extend and interconnect to communicate with other bone cells on the bone surface, influencing bone remodelling.

These cells are difficult to study because they are embedded within the bone, and how these osteocytes relay information to the osteoclasts and osteoblasts and whether purinergic signalling is involved in the process are still not clear. Furthermore, P2X7R-induced pore formation in MLO-Y4 osteocytes was shown to occur in response to fluid shear stress and led to the activation of downstream signals typically involved in mechanically induced bone formation, in particular the release of PGE 2 Yoshida et al.

While a role of P2X7R activation in regulating mechanical load by osteocytes could be speculated, exactly how the activated ion channel creates an intracellular signal capable of an amplified mechanotransduction process remains unclear. Table 1 summarises the effect of P2X7R expression on osteoclasts. Bone resorbing osteoclasts differentiate from the haematopoietic stem cells HSCs and cells of HSC lineage have also been shown to express an array of purinergic receptors Lemoli et al.

Osteoclasts, the bone-resorbing cells, are derived from monocytes and the P2X7R has a complex role in these cells of haematopoietic lineage Fig. P2X7R expression has been shown on authentic osteoclasts generated in vitro from small mammals such as rodents and rabbit Hoebertz et al. However, in a recent study, P2X7R expression in primary mouse osteoclasts has been shown to be differentiation dependent, with higher mRNA and protein levels present in mature, resorbing cells compared with their precursors Brandao-Burch et al.

Fusion of osteoclast precursors is blocked by antagonising P2X7R, possibly as P2X7R pore-mediated ATP release is needed for generation of adenosine which drives fusion. High extracellular ATP levels have been shown to both induce resorption and reduce resorption by initiating apoptosis. Intracellular ATP levels positively regulate survival and resorption. 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. 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. Indeed, Pellegatti et al. In their study, addition of apyrase, and subsequent accumulation of adenosine, drove fusion whereas pharmacological blockade of P2X7R prevented fusion Pellegatti et al.

Therefore, the authors speculate that ATP release via the P2X7R pore is needed for osteoclastic fusion, although the effect may be indirect involving other purinergic receptors. The study suggests that P2X7R regulates the positive effect of LPA in osteoclast fusion and possibly also couples to other osteoclastogenic receptors such as osteoclast stimulatory transmembrane protein OC-STAMP , providing important evidence in support of the role of P2X7R in osteoclastogenesis. P2X7R activation is also thought to be important in the differentiation and survival of osteoclasts in both a paracrine and autocrine manner.

Stimulus by P2X7R specific agonist induces the membrane depolarisation in osteoclasts Naemsch et al. It seems likely that abolishing P2X7R activity would interfere with above signalling activities, thereby negatively influencing osteoclast function by affecting formation of ruffled border and subsequently bone resorption.

In this regard, Hazama et al. Furthermore, the induction of resorption was accompanied by formation of sealing-zone like structures via the reorganisation of pre-existing cytoskeleton and the secretion of lytic granules at the site of osteoclast—matrix attachment. Contrary to this, a recent study using murine bone marrow-derived osteoclasts has reported that extracellular ATP caused disruption of murine osteoclastic cytoskeleton and a subsequent reduction in survival and resorption Miyazaki et al.

Miyazaki et al. Furthermore, either ATP hydrolysis or repletion of intracellular ATP by expression of anti-apoptotic protein Bcl- xL completely reversed the inhibitory effect of extracellular ATP on osteoclast survival. Considering these two studies together suggests that extracellular ATP can act via two distinct mechanisms in controlling osteoclast cell survival — activation of purinergic signalling, particularly the P2X7R, and the control of mitochondrial energy regulation. However, the contradictory effects of ATP in these two studies remain unexplained, although some differences could be species specific Donnelly-Roberts et al.

Activation of P2X7R in osteoclasts is imperative for cell fusion, can lead to initiation of apoptosis and is critical in determining the duration of cell survival and overall resorption Table 1. It could be speculated that basal stimulus may cause a hypo or hyper stimulation of P2X7R due to its genetic variations, culminating in enhanced or reduced osteoclast formation and function respectively.

The P2Y(6) Receptor Stimulates Bone Resorption by Osteoclasts

Clearly a fine balance between the downstream consequences of P2X7R activation is needed and this may be achieved by modulating extracellular ATP concentrations. There are several ways in which ATP can be released from the cell. ATP release in the context of bone has been shown to vary with the differentiation state of the cell mature, bone-forming osteoblasts releasing up to several fold more ATP than undifferentiated, proliferating cells Orriss et al. The role of P2X7R regulated ATP release in response to fluid flow was initially described using human osteoblastic cell lines Rumney et al.

Recently, this has been confirmed using rat calvariae-derived osteoblasts Brandao-Burch et al. Moreover, cultured calvarial osteoblasts from P2X7R null mice were previously shown to release similar amounts of ATP compared with WT cells following external stimulus such as fluid shear Li et al. It is therefore likely that another pathway, such as gap junctions, could be involved.

We have shown that ATP release from human osteoclasts derived from peripheral blood monocytes was reduced in the presence of P2X7R specific antagonists Rumney et al. In support of this, ATP release through the P2X7R pore has been shown to be an important source of extracellular adenosine which acts to promote fusion of human osteoclast monocyte precursors Pellegatti et al. In addition, constitutive release of ATP into extracellular microenvironment between 0.

Phenotype analysis of GSK KO females revealed no overall overt skeletal phenotype, whilst detailed bone analysis revealed a thickening of cortical bones but no differences in their trabecular bone volume compared with WT controls Gartland et al. However, Pfizer KO mice of both genders showed reduced total and cortical bone mineral content BMC and decreased femoral periosteal circumference, abnormalities associated with the effects of disuse on the skeleton Ke et al.

Furthermore, the effect of P2rx7 deletion is more pronounced with age, and histomorphometric analyses showed reduced parameters of bone formation mineralising surface, bone formation rate with an increase in parameters of bone resorption osteoclast number, percent osteoclast surface in KO mice, supportive of a phenotype with an overall reduced bone mass Ke et al.

Compared with the WT controls, these KO mice are also show an apparent reduced sensitivity to mechanical loading Li et al. As such, earlier studies describing the phenotype of P2rx7 KO Table 2 need to be interpreted with caution. Table 2 Bone phenotype of existing P2rx7 KO mice models. Syberg et al. These studies demonstrate the role of the P2X7R in regulation of bone mass and highlight the importance of genetic background when looking at the functional effects of the P2X7R. For a review of use of these mice models in other diseases, please refer to Volonte et al.

In different population-based cohorts, SNPs known to cause a functional change in P2X7R have been correlated with the change in bone strength in postmenopausal women Gartland et al. ArgGln is associated with higher bone loss in women in their postmenopausal years Gartland et al.