Expression and function of the P2X7 receptor in human osteoblasts: The role of NFATc1 transcription factor

Bergamin, Letícia Scussel; Penolazzi, Letizia; Lambertini, Elisabetta; Falzoni, Simonetta; Sarti, Alba Clara; Molle, Caroline M.; Gendron, Fernand‐Pierre; Bonis, Pasquale De; Virgilio, Francesco Di; Piva, Roberta

doi:10.1002/jcp.29891

Cited by 13 publications

(14 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cytosolic free calcium was measured using the fluorescent Ca 2+ indicator Fura‐2‐acetoxymethyl ester (Fura‐2/AM) (Thermo Fischer Scientific; Di Virgilio et al, 2019 ; Bergamin et al, 2021 ). IVD cells (P2) were incubated at 37°C for 20 min in saline solution (125 mM NaCl, 5 mM KCl, 1 mM MgSO 4 , 1 mM NaH 2 PO 4 , 20 mM HEPES, 5.5 mM glucose, and 5 mM NaHCO 3 , pH 7.4), in presence of 1 mM CaCl 2 , and supplemented with 4.0 µM Fura‐2/AM and 250 µM sulfinpyrazone (Sigma‐Aldrich).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The P2X7 purinergic receptor in intervertebral disc degeneration

Penolazzi

Bergamin

Lambertini

et al. 2021

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

Mechanisms involved in the development of intervertebral disc (IVD) degeneration are only partially known, thus making the implementation of effective therapies very difficult. In this study, we investigated P2X7 purinergic receptor (P2X7R), NLRP3 inflammasome, and interleukin (IL)‐1β expression in IVD specimens at different stages of disease progression, and during the in vitro dedifferentiation process of the primary cells derived thereof. We found that P2X7R, NLRP3, and IL‐1β expression was higher in the IVD samples at a more advanced stage of degeneration and in the expanded IVD cells in culture which partially recapitulated the in vivo degeneration process. In IVD cells, the P2X7R showed a striking nuclear localization, while NLRP3 was mainly cytoplasmic. Stimulation with the semiselective P2X7R agonist benzoyl ATP together with lipopolysaccharide treatment triggered P2X7R transfer to the cytoplasm and P2X7R/NLRP3 colocalization. Taken together, these findings support pathophysiological evidence that the degenerated disc is a highly inflamed microenvironment and highlight the P2X7R/NLRP3 axis as a suitable therapeutic target. The immunohistochemical analysis and the assessment of subcellular localization revealed a substantial expression of P2X7R also in normal disc tissue. This gives us the opportunity to contribute to the few studies performed in natively expressed human P2X7R so far, and to understand the possible physiological ATP‐mediated P2X7R homeostasis signaling. Therefore, collectively, our findings may offer a new perspective and pave the way for the exploration of a role of P2X7R‐mediated purinergic signaling in IVD metabolism that goes beyond its involvement in inflammation.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Cytosolic free calcium was measured using the fluorescent Ca 2+ indicator Fura-2-acetoxymethyl ester (Fura-2/AM) (Thermo Fischer Scientific; Di Virgilio et al, 2019;Bergamin et al, 2021). IVD cells (P2)…”

Section: Cytosolic Free Calcium Concentration Measurementsmentioning

confidence: 99%

The P2X7 purinergic receptor in intervertebral disc degeneration

Penolazzi

Bergamin

Lambertini

et al. 2021

Journal Cellular Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…This implies another possible reason, other than radiation exposure, which increases the risk of developing cancer in astronauts during a long period of space travel. The most down-regulated gene, NFATC1 , encodes Nuclear Factor of Activated T Cells 1 and plays important roles in osteoblast differentiation 33 , osteoclastogenesis 34 , T-cell differentiation 35 , lymphatic endothelial development 36 , cardiac valve morphogenesis 37 and tumorigenesis 38 . The downregulation of NFATC1 may result in osteoporosis, immunocompromised conditions, and prostate cancer in astronauts during a prolonged space stay.…”

Section: Resultsmentioning

confidence: 99%

Designing a novel monitoring approach for the effects of space travel on astronauts’ health

Sakharkar

Yang

2022

Preprint

View full text Add to dashboard Cite

Space exploration and extraterrestrial civilization have fascinated humankind since the earliest days of human history. However, it was only until last century that humankind finally began taking significant steps towards these goals by sending astronauts into space, landing on the moon, and building the International Space Station. However, space voyage is very challenging and dangerous, and astronauts are under constant space radiation and microgravity. It has been shown that astronauts are at a high risk of developing a broad range of diseases/disorders. Thus, it is critical to develop a rapid and effective assay to monitor astronauts health in space. In this study, gene expression and correlation patterns were analyzed for 10 astronauts (8 male and 2 female) using the publicly available microarray dataset E-GEOD-74708. We identified 218 differentially expressed genes between In-flight and Pre-flight and noticed that space travel decreased genome regulation and gene correlations across the entire genome, as well as individual signaling pathways. Furthermore, we rationally designed a rapid assay of 32 genes which could be used to monitor astronauts health during space travel. Further studies, including microgravity experiments, are warranted to optimize and validate the proposed assay.

show abstract

“…The DNA promoter of the P2RX7 gene has a series of binding sites for nuclear transcription factors that biologically adapt and modify gene expression 27 . Animal studies have demonstrated that guanosine administration, through its binding site on P2RX7, can inhibit ATP activity and display antidepressant and pro-neurogenic effects in the hippocampus [27][28][29] . In the plasma of treatment-resistant depressed patients, a subpopulation at a high risk of suicide, P2RX7 transcripts were found to correlate with the glucocorticoid receptor, a key stressresponsive transcription factor 30 .…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant P2RX7 expression in neural cells dysregulates neuronal-glial homeostasis and cognition, which may trigger the emergence of depressive symptoms 14,22–26 . The DNA promoter of the P2RX7 gene has a series of binding sites for nuclear transcription factors that biologically adapt and modify gene expression 27 . Animal studies have demonstrated that guanosine administration, through its binding site on P2RX7 , can inhibit ATP activity and display antidepressant and pro-neurogenic effects in the hippocampus 27–29 .…”

Section: Discussionmentioning

confidence: 99%

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

Zhang

Verwer

Heerikhuize

et al. 2022

Preprint

View full text Add to dashboard Cite

Imbalanced purine metabolism is a key neurological basis for suicide and mood disorders (MD), wherein purinergic receptors in stress-sensitive cerebral regions are thought to be differentially activated. A hippocampal network that links the hypothalamus and prefrontal cortex implements an affective sensation of stress. We discovered that the hippocampus encoded fatal suicidal ideations in the dentate gyrus (DG) by a considerable amount of the granule cell nuclei with P2X purinoceptor 7 (P2RX7) expression, irrespective of the underlying MD. Compared to controls, patients with MD showed microglial dyshomeostasis throughout the hippocampal formation. Strikingly, P2Y purinoceptor 12 (P2RY12)-expressing microglia with segmented processes were remarkably present in the superficial layers of the medial entorhinal cortex (mEnt) in individuals with fatal suicidality. In the hypothalamic stress-sensitive nuclei, P2RY12+ microglia were more expressed in the supraoptic nucleus in MD and even higher when fatal suicidality was present. In the prefrontal cortex, P2RX7 transcripts sharply dropped in suicidal individuals, possibly removing the prefrontal inhibition of the hippocampus and hypothalamus. Confounder analysis showed that the suicide-specific molecular features faded when the postmortem delay was prolonged. Our findings imply that fatal suicidality presents with unique neuropathological alterations. The DG and mEnt are two crucial areas for deciphering the suicidal consequences. By including brain samples from legal euthanasia donors, suicide-specific biosignatures can be maximally retained. Decoding the bioactive framework through key genes, brain regions and neurological processes involved in suicide neuropathology may provide novel therapeutic strategies for suicidal individuals who are beyond the reach of mental health care.

show abstract

Expression and function of the P2X7 receptor in human osteoblasts: The role of NFATc1 transcription factor

Cited by 13 publications

References 44 publications

The P2X7 purinergic receptor in intervertebral disc degeneration

The P2X7 purinergic receptor in intervertebral disc degeneration

Designing a novel monitoring approach for the effects of space travel on astronauts’ health

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

Contact Info

Product

Resources

About