Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply

AbstractIn glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.

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Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.9b00623 ◽

2019 ◽

Vol 62 (20) ◽

pp. 9078-9102 ◽

Cited By ~ 10

Author(s):

Matthias Scheiner ◽

Dominik Dolles ◽

Sandra Gunesch ◽

Matthias Hoffmann ◽

Massimo Nabissi ◽

...

Keyword(s):

Cannabinoid Receptor ◽

Neuroprotective Effects ◽

Cannabinoid Receptor 2 ◽

Disease Modifying

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Cannabinoid receptor 2 attenuates microglial accumulation and brain injury following germinal matrix hemorrhage via ERK dephosphorylation in vivo and in vitro

Neuropharmacology ◽

10.1016/j.neuropharm.2015.04.028 ◽

2015 ◽

Vol 95 ◽

pp. 424-433 ◽

Cited By ~ 15

Author(s):

Jun Tang ◽

Yihao Tao ◽

Liang Tan ◽

Liming Yang ◽

Yin Niu ◽

...

Keyword(s):

Brain Injury ◽

Cannabinoid Receptor ◽

Germinal Matrix ◽

Germinal Matrix Hemorrhage ◽

Cannabinoid Receptor 2

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Effects of a Cannabinoid Receptor 2 Selective Antagonist on the Inflammatory Reaction to Titanium Particles In Vivo and In Vitro

Journal of International Medical Research ◽

10.1177/147323001003800616 ◽

2010 ◽

Vol 38 (6) ◽

pp. 2023-2032 ◽

Cited By ~ 7

Author(s):

F Zhou ◽

J Lu ◽

X Zhu ◽

H Mao ◽

H Yang ◽

...

Keyword(s):

Inflammatory Reaction ◽

Cannabinoid Receptor ◽

Cannabinoid Receptor 2 ◽

Selective Antagonist

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Zoledronic Acid Inhibits Osteoclastogenesis in Vitro and in a Mouse Model of Inflammatory Osteolysis

Annals of Otology Rhinology & Laryngology ◽

10.1177/000348940311200907 ◽

2003 ◽

Vol 112 (9) ◽

pp. 780-786 ◽

Cited By ~ 16

Author(s):

Holger Sudhoff ◽

Brian T. Faddis ◽

Jae Y. Jung ◽

Henning Hildmann ◽

Jörg Ebmeyer ◽

...

Keyword(s):

Zoledronic Acid ◽

Bone Marrow Cells ◽

Mineral Apposition Rate ◽

Tunel Staining ◽

Tartrate Resistant Acid Phosphatase ◽

Mouse Bone Marrow ◽

Dependent Manner ◽

Dose Dependent

This study assessed effects of the bisphosphonate zoledronic acid (ZLNA) on osteoclastogenesis. To assess the effect of ZLNA on osteoclast formation in vitro, we cultured mouse bone marrow cells under conditions that promote osteoclastogenesis. Administered at concentrations from 10−6 to 10−9 mol/L, ZLNA led to a dose-dependent inhibition of osteoclastogenesis. Combined TUNEL staining and histochemical staining for tartrate-resistant acid phosphatase showed that ZLNA induced apoptosis in osteoclasts and monocytic precursor cells. To study the effects of ZLNA in vivo, we placed keratin particles onto the surface of the parietal bone of mice to induce localized inflammatory bone resorption. Three experimental groups received daily subcutaneous injections of ZLNA (1, 3, or 10 μg/kg body weight) from 4 days before surgery until 5 days after keratin implantation. The ZLNA significantly reduced osteoclast recruitment in a dose-dependent manner, but did not affect the degree of inflammation or the mineral apposition rate.

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Exosomes derived from human CD34+ stem cells transfected with miR-26a prevent glucocorticoid-induced osteonecrosis of the femoral head by promoting angiogenesis and osteogenesis

Stem Cell Research & Therapy ◽

10.1186/s13287-019-1426-3 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 3

Author(s):

Rongtai Zuo ◽

Lingchi Kong ◽

Mengwei Wang ◽

Wenbo Wang ◽

Jia Xu ◽

...

Keyword(s):

Femoral Head ◽

Rat Model ◽

Biological Effect ◽

Umbilical Vein ◽

Biological Effects ◽

Endothelial Cell Migration ◽

Osteogenic Potential ◽

Alizarin Red ◽

Tube Forming

Abstract Background Damaged endothelial cells and downregulated osteogenic ability are two key pathogenic mechanisms of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). Recent studies suggested that transplantation of CD34+ stem cell-derived exosomes (CD34+-Exos) can treat ischemic diseases by promoting neovascularization and that miR-26a is an important positive regulator of osteogenesis. Moreover, the biological effect of exosomes is closely related to their cargo miRNAs. However, it is not clear whether increasing the abundance of miR-26a in CD34+-Exos will inhibit the progress of GC-induced ONFH. Methods MiR-26a was overexpressed in CD34+-Exos (miR-26a-CD34+-Exos) to increase their osteogenic potential. The angiogenic potential of miR-26a-CD34+-Exos was then examined through evaluations of migration and tube-forming capacities in vitro. In addition, in order to observe the osteogenic effect of miR-26a-CD34+-Exos on bone marrow stromal cells (BMSCs), Alizarin red staining, alkaline phosphatase (ALP) activity assays, and qPCR were carried out. Finally, miR-26a-CD34+-Exos were injected into a GC-induced ONFH rat model to prevent the progress of GC-induced ONFH. The biological effects of miR-26a-CD34+-Exos on the ONFH model were evaluated by micro-CT, angiography, and histological staining. Results Our data showed that miR-26a-CD34+-Exos enhanced human umbilical vein endothelial cell migration and tube-forming capacities. Furthermore, miR-26a-CD34+-Exos strengthened the osteogenic differentiation of BMSCs under the influence of GCs in vitro. Finally, the miR-26a-CD34+-Exos increased the vessel density and trabecular bone integrity of the femoral head in the GC-induced ONFH rat model, which inhibited the progress of ONFH. Conclusions MiR-26a-CD34+-Exos protect the femoral head from damage caused by GCs by strengthening angiogenesis and osteogenesis. The biological effect of miR-26a-CD34+-Exos make them suitable for application in the prevention of GC-induced ONFH.

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Cannabinoid receptor 2 deletion deteriorates myocardial infarction through the down-regulation of AMPK-mTOR-p70S6K signaling-mediated autophagy

Bioscience Reports ◽

10.1042/bsr20180650 ◽

2019 ◽

Vol 39 (4) ◽

Cited By ~ 3

Author(s):

Yao Hu ◽

Yu Tao ◽

Jing Hu

Keyword(s):

Myocardial Infarction ◽

Cell Viability ◽

Signaling Pathway ◽

Cannabinoid Receptor ◽

Cell Counting ◽

Protective Effects ◽

Cannabinoid Receptor 2 ◽

Related Proteins

AbstractCannabinoid receptor 2 (CB2R) has been reported to play an important role in the regulation of pathogenesis and progression of myocardial infarction (MI). Here we tried to investigate its potential mechanisms. The ratio of infarct size in heart issue was detected by TTC staining, and cardiac functions were calculated according to echocardiographic evaluation. Cell viability in cardiomyocytes was investigated by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays. Western blot was used to detect autophagy-related proteins including Beclin-1, LC3, p62, adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)-mammalian target of rapamycin rabbit (mTOR)-p70 ribosomal protein S6 kinase (p70S6K) signaling-related proteins including AMPK, mTOR, p70S6K, and their phosphorylation formation. Rapamycin was used for the induction of autophagy. Cleaved caspase-3 and Bax were detected for analyzing apoptosis. TEM was used for the detection of autophagosomes. We found that CB2R deletion (CB2R KO) largely deteriorated the severity of MI and the cardiac function as well as cell viability of cardiomyocytes. Knocking out CB2R decreased the level of autophagy in heart issues from MI mice as well as cardiomyocytes under oxygen-glucose deprivation (OGD). Furthermore, CB2R dysfunction significantly attenuated the cardiac protective effects of rapamycin both in vivo and in vitro. Finally, we found that CB2R-mediated autophagy was induced by AMPK-mTOR-p70S6K signaling pathway. Our current study demonstrated for the first time that CB2R deletion led to a detrimental effect of MI through the dysfunction of AMPK-mTOR-p70S6K signaling pathway, which might provide a novel insight in the treatment of MI.

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Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Blood ◽

10.1182/blood-2012-06-435362 ◽

2012 ◽

Vol 120 (18) ◽

pp. 3741-3749 ◽

Cited By ~ 43

Author(s):

Sabina Adhikary ◽

Virginia P. Kocieda ◽

Jui-Hung Yen ◽

Ronald F. Tuma ◽

Doina Ganea

Keyword(s):

Matrix Metalloproteinase ◽

Cannabinoid Receptor ◽

Matrix Metalloproteinase 9 ◽

Cns Injury ◽

Migration Assay ◽

Cannabinoid Receptor 2 ◽

Subsequent Decrease ◽

Metalloproteinase 9

Abstract Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9–dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs.

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Cannabidiol in dentistry: a scoping review

10.31219/osf.io/kqp6y ◽

2020 ◽

Author(s):

Carla David ◽

--- ◽

Alejandro Elizalde

Keyword(s):

Scoping Review ◽

Cannabinoid Receptor ◽

Oral Diseases ◽

Scientific Publications ◽

Cannabinoid Receptor 2 ◽

Periodontal Tissues ◽

Positive Therapeutic Effect ◽

Treatment Action

The CBD has many reports of pharmacological effects in various models of pathologies, ranging from inflammatory and neurodegenerative diseases, epilepsy, autoimmune disorders such as multiple sclerosis, arthritis, schizophrenia among others (1). In other medical areas has been developing CBD as great therapeutic possibilities, with much research in pre-clinical phases (laboratory tests), reviews about complex diseases of the oral cavity (2) and expression of endocannabinoids receptors in the dental and periodontal tissues (3,4). However, the use of CBD in the dental field has been poorly studied and limited, and its effects in the treatment of oral diseases are not well known and reported. Similarly, knowing its properties, mechanisms of action and favorable results in the treatment of other oral diseases, it is believed that it may have a positive therapeutic effect in some pathologies of CBD therapeutic dentistry based on scientific publications that discuss its mechanism of treatment action, suggesting possibilities for future investigations on the use of this compound in dentistry in previous years. Therefore, the purpose of this scoping review will be to map the available evidence to provide an overview and technology of the use of cannabidiol, its effects, and related products in dentistry.References.1.PISANTI, Simona, et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacology & therapeutics, vol. 175, p. 133-150, 2017. DOI: https://doi.org/10.1016/j.pharmthera.2017.02.041. 2.CUBA, L. F., et al. Cannabidiol: an alternative therapeutic agent for oral mucositis?. Journal of clinical pharmacy and therapeutics, 2017, vol. 42, no 3, p. 245-250.3. Abidi, Ammaar H., et al. "Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts." Archives of oral biology 87 (2018): 79-85.4.KONERMANN, Anna, et al. In vivo and in vitro identification of endocannabinoid signaling in periodontal tissues and their potential role in local pathophysiology. Cellular and molecular neurobiology, 2017, vol. 37, no 8, p. 1511-1520.

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Targeting CYP2J2 to Enhance the Anti-Glioma Efficacy of Cannabinoid Receptor 2 Stimulation by Inhibiting the Pro-Angiogenesis Function of M2 Microglia

Frontiers in Oncology ◽

10.3389/fonc.2020.574277 ◽

2020 ◽

Vol 10 ◽

Author(s):

Xuejiao Lei ◽

Xuezhu Chen ◽

Yulian Quan ◽

Yihao Tao ◽

Junlong Li

Keyword(s):

Cellular Proliferation ◽

Cannabinoid Receptor ◽

Tube Formation ◽

Epoxyeicosatrienoic Acid ◽

Cannabinoid Receptor 2 ◽

Cancer Management ◽

Qrt Pcr ◽

M2 Microglia

Enhancing the therapeutic efficacy of anti-tumor drugs is essential for cancer management. Although cannabinoid receptor 2 (CB2R) stimulation exerts anti-tumor action in glioma cells by regulating cellular proliferation, differentiation, or apoptosis, selective CB2R agonist alone does not achieve a satisfactory therapeutic outcome. Herein, we aimed to evaluate the possible strategy for enhancing the anti-glioma efficacy of JWH133, a selective CB2R agonist. In this study, immunofluorescence and qRT-PCR were used to investigate microglia polarization. Tumor growth was monitored via bioluminescent imaging using the IVIS Spectrum System. The angiogenesis of human brain microvascular endothelial cells (HBMECs) was detected by the tube formation assay. qRT-PCR was used to investigate cytochrome P450 2J2 (CYP2J2) and 11,12-epoxyeicosatrienoic acid (11,12-EET) expression. Our results showed that administration of JWH133 significantly promoted microglial M2 polarization both in vitro and in vivo. The medium supernatant of M2 microglia induced by JWH133 treatment facilitated angiogenesis of HBMECs. CYP2J2 expression and 11,12-EET release in the supernatant of JWH133-induced M2 microglia were significantly upregulated. Treatment with 11,12-EET prompted HBMEC angiogenesis and glioma growth. CYP2J2 knockdown restrained the release of 11,12-EET and significantly enhanced the anti-tumor effect of JWH133 on glioma. This study showed that targeting CYP2J2 might be a beneficial strategy to enhance the anti-glioma efficacy of JWH133 by inhibiting the pro-angiogenesis function of M2 microglia.

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