scholarly journals P2Y Receptors in Bone - Anabolic, Catabolic, or Both?

2022 ◽  
Vol 12 ◽  
Author(s):  
Yuhan Zhou ◽  
Hector M. Arredondo ◽  
Ning Wang
Keyword(s):  
Bone Cells ◽  
P2y Receptors ◽  
Extracellular Nucleotides ◽  
Dual Function ◽  
Bone Homeostasis ◽  
Bone Biology ◽  
New Research ◽  
G Protein Coupled ◽  
Targeting Strategy ◽  
Bone Physiology

P2Y receptors, including eight subtypes, are G protein-coupled receptors that can be activated by extracellular nucleotides. Nearly all P2Y receptors are expressed in bone cells, suggesting their involvements in bone physiology and pathology. However, their exact roles in bone homeostasis are not entirely clear. Therefore, this mini review summarizes new research developments regarding individual P2Y receptors and their roles in bone biology, particularly detailing those which execute both anabolic and catabolic functions. This dual function has highlighted the conundrum of pharmacologically targeting these P2Y receptors in bone-wasting diseases. Further research in finding more precise targeting strategy, such as promoting anabolic effects via combining with physical exercise, should be prioritized.

scholarly journals HO-1 in Bone Biology: Potential Therapeutic Strategies for Osteoporosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Xueman Zhou ◽  
Wenxiu Yuan ◽  
Xin Xiong ◽  
Zhenzhen Zhang ◽  
Jiaqi Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Cells ◽  
Current Knowledge ◽  
Bone Microarchitecture ◽  
Osteoporosis Treatment ◽  
Bone Fragility ◽  
Heme Oxygenase 1 ◽  
Bone Homeostasis ◽  
Mass Reduction ◽  
Bone Biology

Osteoporosis is a prevalent bone disorder characterized by bone mass reduction and deterioration of bone microarchitecture leading to bone fragility and fracture risk. In recent decades, knowledge regarding the etiological mechanisms emphasizes that inflammation, oxidative stress and senescence of bone cells contribute to the development of osteoporosis. Studies have demonstrated that heme oxygenase 1 (HO-1), an inducible enzyme catalyzing heme degradation, exhibits anti-inflammatory, anti-oxidative stress and anti-apoptosis properties. Emerging evidence has revealed that HO-1 is critical in the maintenance of bone homeostasis, making HO-1 a potential target for osteoporosis treatment. In this Review, we aim to provide an introduction to current knowledge of HO-1 biology and its regulation, focusing specifically on its roles in bone homeostasis and osteoporosis. We also examine the potential of HO-1-based pharmacological therapeutics for osteoporosis and issues faced during clinical translation.

scholarly journals Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective

2021 ◽  
Vol 12 ◽  
Author(s):  
Jean M. Kanellopoulos ◽  
Cássio Luiz Coutinho Almeida-da-Silva ◽  
Sirje Rüütel Boudinot ◽  
David M. Ojcius
Keyword(s):  
Plasma Membrane ◽  
P2y Receptors ◽  
Potential Interaction ◽  
The Body ◽  
Extracellular Nucleotides ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Functional Features ◽  
G Protein Coupled

Extracellular nucleotides are important mediators of activation, triggering various responses through plasma membrane P2 and P1 receptors. P2 receptors are further subdivided into ionotropic P2X receptors and G protein-coupled P2Y receptors. P2X4 is an ATP-gated cation channel broadly expressed in most tissues of the body. Within the P2X family, P2X4 has a unique subcellular distribution, being preferentially localized in lysosomes. In these organelles, high ATP concentrations do not trigger P2X4 because of the low pH. However, when the pH increases to 7.4, P2X4 can be stimulated by intra-lysosomal ATP, which is in its active, tetra-anionic form. Elucidation of P2X4, P2X3 and P2X7 structures has shed some light on the functional differences between these purinergic receptors. The potential interaction between P2X4 and P2X7 has been extensively studied. Despite intensive effort, it has not been possible yet to determine whether P2X4 and P2X7 interact as heterotrimers or homotrimers at the plasma membrane. However, several publications have shown that functional interactions between P2X4 and P2X7 do occur. Importantly, these studies indicate that P2X4 potentiates P2X7-dependent activation of inflammasomes, leading to increased release of IL-1β and IL-18. The role of P2X4 in various diseases could be beneficial or deleterious even though the pathophysiological mechanisms involved are still poorly defined. However, in diseases whose physiopathology involves activation of the NLRP3 inflammasome, P2X4 was found to exacerbate severity of disease. The recent production of monoclonal antibodies specific for the human and mouse P2X4, some of which are endowed with agonist or antagonist properties, raises the possibility that they could be used therapeutically. Analysis of single nucleotide polymorphisms of the human P2RX4 gene has uncovered the association of P2RX4 gene variants with susceptibility to several human diseases.

scholarly journals Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Rinaldo Florencio-Silva ◽  
Gisela Rodrigues da Silva Sasso ◽  
Estela Sasso-Cerri ◽  
Manuel Jesus Simões ◽  
Paulo Sérgio Cerri
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Tissue ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Current Data ◽  
Bone Diseases ◽  
Bone Homeostasis ◽  
Bone Biology ◽  
Structure And Functions

Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling.

scholarly journals Autophagy in bone homeostasis and the onset of osteoporosis

Bone Research ◽  
2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Xing Yin ◽  
Chenchen Zhou ◽  
Jingtao Li ◽  
Renkai Liu ◽  
Bing Shi ◽  
...  
Keyword(s):  
Stress Responses ◽  
Bone Cells ◽  
Therapeutic Potential ◽  
Bone Diseases ◽  
Bone Homeostasis ◽  
Functional Studies ◽  
Evolutionarily Conserved ◽  
Intracellular Process ◽  
Cellular Components ◽  
Bone Physiology

Abstract Autophagy is an evolutionarily conserved intracellular process, in which domestic cellular components are selectively digested for the recycling of nutrients and energy. This process is indispensable for cell homeostasis maintenance and stress responses. Both genetic and functional studies have demonstrated that multiple proteins involved in autophagic activities are critical to the survival, differentiation, and functioning of bone cells, including osteoblasts, osteocytes, and osteoclasts. Dysregulation at the level of autophagic activity consequently disturbs the balance between bone formation and bone resorption and mediates the onset and progression of multiple bone diseases, including osteoporosis. This review aims to introduce the topic of autophagy, summarize the understanding of its relevance in bone physiology, and discuss its role in the onset of osteoporosis and therapeutic potential.

Mechanisms of P2X7 receptor-mediated ERK1/2 phosphorylation in human astrocytoma cells

2003 ◽  
Vol 284 (2) ◽  
pp. C571-C581 ◽  
Author(s):  
Fernand-Pierre Gendron ◽  
Joseph T. Neary ◽  
Patty M. Theiss ◽  
Grace Y. Sun ◽  
Fernando A. Gonzalez ◽  
...  
Keyword(s):  
P2y Receptors ◽  
P2x Receptors ◽  
Extracellular Nucleotides ◽  
Phosphatidylinositol 3 Kinase ◽  
Brain Functions ◽  
Astrocytoma Cells ◽  
Human Astrocytoma ◽  
G Protein Coupled ◽  
Human Astrocytoma Cells ◽  
Protein Kinase Cδ

Astrocytes are involved in normal and pathological brain functions, where they become activated and undergo reactive gliosis. Astrocytes have been shown to respond to extracellular nucleotides via the activation of P2 receptors, either G protein-coupled P2Y receptors or P2X receptors that are ligand-gated ion channels. In this study, we have examined the manner in which activation of the P2X7 nucleotide receptor, an extracellular ATP-gated ion channel expressed in astrocytes, can lead to the phosphorylation of ERK1/2. Results showed that the P2X7 receptor agonist 2′,3′- O-(4-benzoyl)benzoyl-ATP induced ERK1/2 phosphorylation in human astrocytoma cells overexpressing the recombinant rat P2X7 receptor (rP2X7-R), a response that was inhibited by the P2X7 receptor antagonist, oxidized ATP. Other results suggest that rP2X7-R-mediated ERK1/2 phosphorylation was linked to the phosphorylation of the proline-rich/Ca2+-activated tyrosine kinase Pyk2, c-Src, phosphatidylinositol 3′-kinase, and protein kinase Cδ activities and was dependent on the presence of extracellular Ca2+. These results support the hypothesis that the P2X7 receptor and its signaling pathways play a role in astrocyte-mediated inflammation and neurodegenerative disease.

Lactoferrin in Bone Tissue Regeneration

2020 ◽  
Vol 27 (6) ◽  
pp. 838-853 ◽  
Author(s):  
Madalina Icriverzi ◽  
Valentina Dinca ◽  
Magdalena Moisei ◽  
Robert W. Evans ◽  
Mihaela Trif ◽  
...  
Keyword(s):  
Bone Tissue ◽  
Tissue Regeneration ◽  
Bone Cells ◽  
Bone Diseases ◽  
Biologically Active Compounds ◽  
Biologically Active ◽  
Bone Tissue Regeneration ◽  
Bone Homeostasis ◽  
Active Compounds

: Among the multiple properties exhibited by lactoferrin (Lf), its involvement in bone regeneration processes is of great interest at the present time. A series of in vitro and in vivo studies have revealed the ability of Lf to promote survival, proliferation and differentiation of osteoblast cells and to inhibit bone resorption mediated by osteoclasts. Although the mechanism underlying the action of Lf in bone cells is still not fully elucidated, it has been shown that its mode of action leading to the survival of osteoblasts is complemented by its mitogenic effect. Activation of several signalling pathways and gene expression, in an LRPdependent or independent manner, has been identified. Unlike the effects on osteoblasts, the action on osteoclasts is different, with Lf leading to a total arrest of osteoclastogenesis. : Due to the positive effect of Lf on osteoblasts, the potential use of Lf alone or in combination with different biologically active compounds in bone tissue regeneration and the treatment of bone diseases is of great interest. Since the bioavailability of Lf in vivo is poor, a nanotechnology- based strategy to improve the biological properties of Lf was developed. The investigated formulations include incorporation of Lf into collagen membranes, gelatin hydrogel, liposomes, loading onto nanofibers, porous microspheres, or coating onto silica/titan based implants. Lf has also been coupled with other biologically active compounds such as biomimetic hydroxyapatite, in order to improve the efficacy of biomaterials used in the regulation of bone homeostasis. : This review aims to provide an up-to-date review of research on the involvement of Lf in bone growth and healing and on its use as a potential therapeutic factor in bone tissue regeneration.

scholarly journals FRI0376 EFFECT OF CARBAMYLATED LOW-DENSITY LIPOPROTEINS ON BONE CELLS HOMEOSTASIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 784.2-785
Author(s):  
B. Lucchino ◽  
M. Leopizzi ◽  
T. Colasanti ◽  
V. DI Maio ◽  
C. Alessandri ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Low Density Lipoproteins ◽  
Tartrate Resistant Acid Phosphatase ◽  
Low Density ◽  
Bone Homeostasis ◽  
Research Support ◽  
Erosive Disease

Background:Carbamylation is a post-translational modification occurring under several conditions such as uremia, smoking and chronic inflammation as in rheumatoid arthritis (RA). Low-density lipoproteins (LDL) represent a target of carbamylation. Carbamylated-LDL (cLDL) have an increased inflammatory and atherogenic potential. Growing evidence supports an influence of modified lipids on bone cells homeostasis. However, the role of cLDL on bone cells physiology is still unknown.Objectives:Considering the rate of carbamylation and the role of anti-carbamylated proteins antibodies as markers of erosive disease in RA, the purpose of this study is to investigate the effect of cLDL on bone homeostasis.Methods:In-vitrocarbamylation of LDL was performed as previously described by Ok et al. (Kidney Int. 2005). Briefly, native LDL (nLDL) were treated with potassium cyanate (KOCN) for 4 hours, followed by excessive dialysis for 36 hours to remove KOCN. Both osteoclasts (OCs) and osteoblasts (OBLs) were treated at baseline with 20 μg/ml, 100 μg/ml and 200 μg/ml of cLDL or nLDL. To induce osteoclast differentiation, CD14+ monocytes were isolated from peripheral blood of healthy donors by magnetic microbeads separation and then cultured on a 96-wells plate in DMEM media supplemented with RANKL and M-CSF. After 10 days cells were fixed, stained for tartrate-resistant acid phosphatase (TRAP), a marker of OC differentiation, and counted. OBLs were isolated from bone specimens of 3 patients who had undergone to knee or hip arthroplasty for osteoarthritis and treated for 5 days with different concentrations of cLDL and nLDL. OBLs were fixed and stained for alkaline phosphatase positive activity (ALP), a marker of osteogenic differentiation. Total RNA was extracted from cell lysates. Copies of single-stranded complementary DNA (cDNA) were synthesized and analyzed by real-time PCR to evaluate RANKL and Osteoprotegerin (OPG) mRNA expression levels.Results:In OCLs culture, cLDL significantly decreased the number of OC compared to untreated cells (200 μg/ml p=0,0015) and nLDL treated cells (200 μg/ml p= 0,011; 20 μg/ml p= 0,0014) (Fig 1). Moreover, treatment with cLDL induced an increase of not terminally differentiated OCs, reduced dimensions of OCs, less intense TRAP staining and vacuolization (Fig 2). In OBLs culture, cLDL (20, 100 μg/ml) significantly reduced the ALP activity of OBLs compared with untreated cells (p<0.05) (Fig 3). nLDL did not affect the ALP expression. Treatment with cLDL stimulated RANKL mRNA expression in osteoblasts increasing the RANKL/OPG ratio (Fig 4).Fig 1.Fig 2.Fig 3.Fig 4.Conclusion:cLDL induce a significant depression of OC and OBL differentiation. Moreover, cLDL increase RANKL expression in OBL, unbalancing bone tissue turnover towards bone resorption. Accordingly, cLDL could be implicated in the bone loss characterizing several conditions associated to an increased carbamylation, such as RADisclosure of Interests:Bruno Lucchino: None declared, Martina Leopizzi: None declared, Tania Colasanti: None declared, Valeria Di Maio: None declared, cristiano alessandri Grant/research support from: Pfizer, Guido Valesini: None declared, fabrizio conti Speakers bureau: BMS, Lilly, Abbvie, Pfizer, Sanofi, Manuela Di Franco: None declared, Francesca Romana Spinelli Grant/research support from: Pfizer, Consultant of: Novartis, Gilead, Lilly, Sanofi, Celgene, Speakers bureau: Lilly

scholarly journals Protocol of Co-Culture of Human Osteoblasts and Osteoclasts to Test Biomaterials for Bone Tissue Engineering

2022 ◽  
Vol 5 (1) ◽  
pp. 8
Author(s):  
Giorgia Borciani ◽  
Giorgia Montalbano ◽  
Nicola Baldini ◽  
Chiara Vitale-Brovarone ◽  
Gabriela Ciapetti
Keyword(s):  
Tissue Engineering ◽  
Bone Tissue Engineering ◽  
Bone Tissue ◽  
Bone Cells ◽  
Bone Cell ◽  
Seeding Density ◽  
Bone Homeostasis ◽  
Bone Microenvironment

New biomaterials and scaffolds for bone tissue engineering (BTE) applications require to be tested in a bone microenvironment reliable model. On this assumption, the in vitro laboratory protocols with bone cells represent worthy experimental systems improving our knowledge about bone homeostasis, reducing the costs of experimentation. To this day, several models of the bone microenvironment are reported in the literature, but few delineate a protocol for testing new biomaterials using bone cells. Herein we propose a clear protocol to set up an indirect co-culture system of human-derived osteoblasts and osteoclast precursors, providing well-defined criteria such as the cell seeding density, cell:cell ratio, the culture medium, and the proofs of differentiation. The material to be tested may be easily introduced in the system and the cell response analyzed. The physical separation of osteoblasts and osteoclasts allows distinguishing the effects of the material onto the two cell types and to evaluate the correlation between material and cell behavior, cell morphology, and adhesion. The whole protocol requires about 4 to 6 weeks with an intermediate level of expertise. The system is an in vitro model of the bone remodeling system useful in testing innovative materials for bone regeneration, and potentially exploitable in different application fields. The use of human primary cells represents a close replica of the bone cell cooperation in vivo and may be employed as a feasible system to test materials and scaffolds for bone substitution and regeneration.

scholarly journals Geoffrey Burnstock. 10 May 1929—3 June 2020

2021 ◽  
Author(s):  
R. Alan North ◽  
Marcello Costa
Keyword(s):  
P2y Receptors ◽  
Autonomic Nerves ◽  
Purine Nucleotides ◽  
Biomedical Scientist ◽  
Signalling Molecule ◽  
University College London ◽  
University Colleges ◽  
The University ◽  
G Protein Coupled ◽  
Extracellular Signalling

Geoffrey Burnstock was a biomedical scientist who gained renown for his discovery that adenosine 5′-triphosphate (ATP) functions as an extracellular signalling molecule. Born in London and educated at King's and University colleges, he did postdoctoral work at Mill Hill and Oxford. He moved in 1959 to the Department of Zoology at the University of Melbourne because he sensed there a greater freedom to challenge established thinking in physiology. His group found that transmission from sympathetic and parasympathetic autonomic nerves to smooth muscle was in some places not mediated by the accepted chemical messengers (noradrenaline and acetylcholine). He amassed evidence that ATP was this non-adrenergic, non-cholinergic transmitter, using biochemical, histological and electrophysiological approaches: heretically, he styled this ‘purinergic transmission’. Geoff further upset dogma in the 1970s by proposing ‘co-transmission’ in which some nerves released ATP in addition to either noradrenaline or acetylcholine. He distinguished pharmacologically P1 receptors (activated best by adenosine and blocked by xanthines) and P2 receptors (activated best by purine nucleotides such as ATP) and he proposed in 1985 that the latter embraced P2X (ion channel) and P2Y (G protein-coupled) subtypes: about 10 years later these categories were substantiated by cDNA cloning. From 1975 until his retirement in 1997, Geoff was head of the Department of Anatomy and Embryology at University College London (UCL), which he developed energetically into a large and strong research department. Later, as head of the Autonomic Research Institute at the Royal Free (part of UCL), he continued to collaborate extensively, and founded several journals and international professional societies. He widely sought clinical benefit for his discoveries, and both P2X and P2Y receptors have been developed as the targets of useful therapeutics (gefapixant, clopidogrel). Geoff was proud of his modest, rather humble, background and eschewed formality. He may have smiled when his early discoveries were met with cynicism, even ridicule (‘pure-imagine’ transmission noted one amusing critic), but this just reinforced his resolve and encouraged his encyclopaedic oeuvre.

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