scholarly journals The Role of Cannabinoids in Bone Metabolism: A New Perspective for Bone Disorders

2021 ◽  
Vol 22 (22) ◽  
pp. 12374
Author(s):  
Federica Saponaro ◽  
Rebecca Ferrisi ◽  
Francesca Gado ◽  
Beatrice Polini ◽  
Alessandro Saba ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Bone Cells ◽  
Local Level ◽  
Bone Diseases ◽  
Skeletal Health ◽  
Messenger Molecules ◽  
New Perspective ◽  
Endogenous Cannabinoid

Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous remodeling process needs to occur involving the coordinated action of different types of bone cells: osteoblasts (OBs), which have the capacity to produce newly formed bone, and osteoclasts (OCs), which can remove old bone. Bone remodeling is a highly regulated process that requires many hormones and messenger molecules, both at the systemic and the local level. The whole picture is still not fully understood, and the role of novel actors, such as the components of the endocannabinoids system (ECS), including endogenous cannabinoid ligands (ECs), cannabinoid receptors (CBRs), and the enzymes responsible for endogenous ligand synthesis and breakdown, is extremely intriguing. This article reviews the connection between the ECS and skeletal health, supporting the potential use of cannabinoid receptor ligands for the treatment of bone diseases associated with accelerated osteoclastic bone resorption, including osteoporosis and bone metastasis.

scholarly journals Role of the Endocannabinoid/Endovanilloid System in the Modulation of Osteoclast Activity in Paget’s Disease of Bone

2021 ◽  
Vol 22 (18) ◽  
pp. 10158
Author(s):  
Marco Paoletta ◽  
Antimo Moretti ◽  
Sara Liguori ◽  
Alessandra Di Paola ◽  
Chiara Tortora ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Disease Model ◽  
Paget’S Disease ◽  
Paget's Disease ◽  
Bone Diseases ◽  
Tartrate Resistant Acid Phosphatase ◽  
Metabolic Bone Disorder ◽  
Metabolic Bone

The role of the endocannabinoid/endovanilloid (EC/EV) system in bone metabolism has recently received attention. Current literature evidences the modulation of osteoclasts and osteoblasts through the activation or inhibition of cannabinoid receptors in various pathological conditions with secondary involvement of bone tissue. However, this role is still unclear in primary bone diseases. Paget’s disease of the bone (PDB) could be considered a disease model for analyzing the role of the EC/EV system on osteoclasts (OCs), speculating the potential use of specific agents targeting this system for managing metabolic bone disorders. The aim of the study is to analyze OCs expression of EC/EV system in patients with PDB and to compare OCs activity between this population and healthy people. Finally, we investigate whether specific agents targeting EC/EV systems are able to modulate OCs activity in this metabolic bone disorder. We found a significant increase in cannabinoid receptor type 2 (CB2) protein expression in patients with PDB, compared to healthy controls. Moreover, we found a significant reduction in multi-nucleated tartrate-resistant acid phosphatase (TRAP)–positive OCs and resorption areas after treatment with JWH-133. CB2 could be a molecular target for reducing the activity of OCs in PDB, opening new therapeutic scenarios for the management of this condition.

Molecular Modeling of an Orphan GPR18 Receptor

2019 ◽  
Vol 16 (10) ◽  
pp. 1167-1174 ◽  
Author(s):  
Kamil J. Kuder ◽  
Tadeusz Karcz ◽  
Maria Kaleta ◽  
Katarzyna Kiec-Kononowicz
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Glycine Receptor ◽  
Homology Model ◽  
Orphan Receptor ◽  
Receptor Ligands ◽  
Orphan Receptors ◽  
Inactive Form ◽  
Starting Point ◽  
Endogenous Cannabinoid

Background: : One of the best known to date GPCR class A (Rhodopsin) includes more than 100 orphan receptors for which the endogenous ligand is not known or is unclear. One of them is N-arachidonyl glycine receptor, named GPR18, a receptor that has been reported to be activated by Δ9-THC, endogenous cannabinoid receptors agonist anandamide and other cannabinoid receptor ligands suggesting it could be considered as third cannabinoid receptor. GPR18 activity, as well as its distribution might suggest usage of GPR18 ligands in treatment of endometriosis, cancer, and neurodegenerative disorders. Yet, so far only few GPR18 antagonists have been described, thus only ligand-based design approaches appear to be most useful to identify new ligands for this orphan receptor. Methods: : Main goal of this study, GPR18 inactive form homology model was built on the basis of the evolutionary closest homologous template: Human P2Y1 Receptor crystal structure. Results: : Obtained model was further evaluated and showed active/nonactive ligands differentiating properties with acceptable confidence. Moreover, it allowed for preliminary assessment of proteinligand interactions for a set of previously described ligands. Conclusion:: Thus collected data might serve as a starting point for a discovery of novel, active GPR18 blocking ligands.

The endogenous cannabinoid receptor ligand, anandamide, inhibits the motor behavior: role of nigrostriatal dopaminergic neurons

Life Sciences ◽  
1995 ◽  
Vol 56 (23-24) ◽  
pp. 2033-2040 ◽  
Author(s):  
J. Romero ◽  
L. Garcia ◽  
M. Cebeira ◽  
D. Zadrozny ◽  
J.J. Fernández-Ruiz ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Cannabinoid Receptor ◽  
Motor Behavior ◽  
Receptor Ligand ◽  
Endogenous Cannabinoid

scholarly journals GPR18, GPR55 and GPR119 (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Stephen P.H. Alexander ◽  
Andrew J. Irving
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Structural Similarity ◽  
Synthetic Cannabinoid ◽  
Receptor Ligands ◽  
Orphan Status ◽  
Endogenous Cannabinoid

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB1 and CB2 cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands [98]. Although there are multiple reports to indicate that GPR18, GPR55 and GPR119 can be activated in vitro by N-arachidonoylglycine, lysophosphatidylinositol and N-oleoylethanolamide, respectively, there is a lack of evidence for activation by these lipid messengers in vivo. As such, therefore, these receptors retain their orphan status.

scholarly journals Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 810
Author(s):  
Camille Jacques ◽  
Robel Tesfaye ◽  
Melanie Lavaud ◽  
Steven Georges ◽  
Marc Baud’huin ◽  
...  
Keyword(s):  
Bone Cells ◽  
Osteoblastic Differentiation ◽  
Bone Diseases ◽  
Tumor Suppressor Protein ◽  
Genomic Integrity ◽  
Potential Implication ◽  
Cycle Arrest ◽  
Transcriptional Regulatory ◽  
Bone Sarcomas

The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression.

scholarly journals CB1 cannabinoid receptors are involved in neuroprotection via NF-κB inhibition

2005 ◽  
Vol 25 (4) ◽  
pp. 477-484 ◽  
Author(s):  
David Panikashvili ◽  
Raphael Mechoulam ◽  
Sara M Beni ◽  
Alexander Alexandrovich ◽  
Esther Shohami
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Infarct Volume ◽  
Closed Head Injury ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Edema Formation ◽  
Neurobehavioral Function ◽  
High Doses

We reported earlier that closed head injury (CHI) in mice causes a sharp elevation of brain 2-arachidonoylglycerol (2-AG) levels, and that exogenous 2-AG reduces brain edema, infarct volume and hippocampal death and improved clinical recovery after CHI. The beneficial effect of 2-AG was attenuated by SR141716A, a CB1 cannabinoid receptor antagonist, albeit at relatively high doses. In the present study, we further explored the role of CB1 receptors in mediating 2-AG neuroprotection. CB1 receptor knockout mice (CB1(−/−)) showed minor spontaneous recovery at 24 h after CHI, in contrast to the significant improvement in neurobehavioral function seen in wild-type (WT) mice. Moreover, administration of 2-AG did not improve neurological performance and edema formation in the CB1(−/−) mice. In addition, 2-AG abolished the three- to four-fold increase of nuclear factor κB (NF-κB) transactivation, at 24 h after CHI in the WT mice, while it had no effect on NF-κB in the CB1(−/−) mice, which was as high as in the WT vehicle-treated mice. We thus propose that 2-AG exerts its neuroprotection after CHI, at least in part, via CB1 receptor-mediated mechanisms that involve inhibition of intracellular inflammatory signaling pathways.

scholarly journals Amygdalar CB2 cannabinoid receptor mediates fear extinction deficits promoted by orexin-A/hypocretin-1

2021 ◽  
Author(s):  
Marc Ten-Blanco ◽  
África Flores ◽  
Inmaculada Pereda-Pérez ◽  
Fabiana Piscitelli ◽  
Cristina Izquierdo-Luengo ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Cannabinoid Receptor ◽  
Fear Extinction ◽  
Post Traumatic Stress ◽  
Orexin A ◽  
Post Traumatic ◽  
Learned Fear ◽  
Endogenous Cannabinoid ◽  
Endogenous Cannabinoid System

Background and purpose: Anxiety is often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear remain unknown. Experimental approach: We investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. Behavioural pharmacology, neurochemical, molecular and genetic approaches were used. Key results: The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. Conclusions and implications: We reveal that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism may pave the way towards novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.

scholarly journals Modulation of Fear and Anxiety by the Endogenous Cannabinoid System

CNS Spectrums ◽  
2007 ◽  
Vol 12 (3) ◽  
pp. 211-220 ◽  
Author(s):  
Jasmeer P. Chhatwal ◽  
Kerry J. Ressler
Keyword(s):  
Cannabinoid Receptor ◽  
Conditioned Fear ◽  
Neural Circuitry ◽  
Cannabinoid System ◽  
Fear And Anxiety ◽  
New Treatments ◽  
Endogenous Cannabinoid ◽  
Remarkable Progress ◽  
Endogenous Cannabinoid System

ABSTRACTThe last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the role of the cannabinoid system in modulating the neural circuitry that mediates anxiety and fear responses. This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the acquisition, expression, and extinction of conditioned fear as a model of human anxiety. Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.

scholarly journals Piezo Channels: Awesome Mechanosensitive Structures in Cellular Mechanotransduction and Their Role in Bone

2021 ◽  
Vol 22 (12) ◽  
pp. 6429
Author(s):  
Xia Xu ◽  
Shuyu Liu ◽  
Hua Liu ◽  
Kang Ru ◽  
Yunxian Jia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Cells ◽  
Current Knowledge ◽  
Bone Diseases ◽  
Mechanical Forces ◽  
Mechanical Stimuli ◽  
Cellular Mechanotransduction ◽  
Piezo Channels ◽  
And Function

Piezo channels are mechanosensitive ion channels located in the cell membrane and function as key cellular mechanotransducers for converting mechanical stimuli into electrochemical signals. Emerged as key molecular detectors of mechanical forces, Piezo channels’ functions in bone have attracted more and more attention. Here, we summarize the current knowledge of Piezo channels and review the research advances of Piezo channels’ function in bone by highlighting Piezo1′s role in bone cells, including osteocyte, bone marrow mesenchymal stem cell (BM-MSC), osteoblast, osteoclast, and chondrocyte. Moreover, the role of Piezo channels in bone diseases is summarized.

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