Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 <scp>MAPK</scp>

Kang, Mi Young; Lee, Jongsung; Park, See‐Hyoung

doi:10.1002/tox.22996

Cited by 21 publications

(10 citation statements)

References 49 publications

(91 reference statements)

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“…The MAPK family includes three isoforms: extracellular signaling regulatory kinase (ERK), c-jun amino-terminal kinase (JNK), and p38 kinase (p38 MAPK), which are involved in inflammatory processes ( 32 ). In our findings, LPS inhibited the activation of p38 MAPK signaling pathway, while CBD activated p38 MAPK signaling pathway in an inflammatory environment, which was consistent with previous studies showed that CBD promoted MG-63 cells osteogenesis differentiation through p38 MAPK pathways in non-inflammatory microenvironment ( 34 ). Canna-binoids and their correspondent receptors could activate downstream MAPK isoforms ( 35 ).…”

Section: Discussionsupporting

confidence: 92%

Cannabidiol Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in the Inflammatory Microenvironment via the CB2-dependent p38 MAPK Signaling Pathway

Jin

Sun

et al. 2022

Int J Stem Cells

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Background and Objectives: Chronic inflammation of bone tissue often results in bone defects and hazards to tissue repair and regeneration. Cannabidiol (CBD) is a natural cannabinoid with multiple biological activities, including anti-inflammatory and osteogenic potential. This study aimed to investigate the efficacy and mechanisms of CBD in the promotion of bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation in the inflammatory microenvironment. Methods and Results: BMSCs isolated from C57BL/6 mice, expressed stem cell characteristic surface markers and presented multidirectional differentiation potential. The CCK-8 assay was applied to evaluate the effects of CBD on BMSCs' vitality, and demonstrating the safety of CBD on BMSCs. Then, BMSCs were stimulated with lipopolysaccharide (LPS) to induce inflammatory microenvironment. We found that CBD intervention down-regulated mRNA expression levels of inflammatory cytokines and promoted cells proliferation in LPS-treated BMSCs, also reversed the protein and mRNA levels downregulation of osteogenic markers caused by LPS treatment. Moreover, CBD intervention activated the cannabinoid receptor 2 (CB2) and the p38 mitogen-activated protein kinase (MAPK) signaling pathway. While AM630, a selective CB2 inhibitor, reduced phosphorylated (p)-p38 levels. In addition, AM630 and SB530689, a selective p38 MAPK inhibitor, attenuated the enhancement of osteogenic markers expression levels by CBD in inflammatory microenvironment, respectively. Conclusions: CBD promoted osteogenic differentiation of BMSCs via the CB2/p38 MAPK signaling pathway in the inflammatory microenvironment.

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Section: Discussionsupporting

confidence: 92%

Cannabidiol Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in the Inflammatory Microenvironment via the CB2-dependent p38 MAPK Signaling Pathway

Jin

Sun

et al. 2022

Int J Stem Cells

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“…In rats, CBD was shown to improve fracture healing ( 48 ) and bone mineral density ( 49 ). Furthermore, CBD induced differentiation in two kinds of human osteoblast-like cell lines, demonstrating its potential to promote bone formation ( 50 ), as well as promoting osteogenic differentiation in bone marrow mesenchymal stem cells ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs

Bradley¹,

Young²,

Bakke³

et al. 2022

Front. Vet. Sci.

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Cannabidiol (CBD) containing dog food and treats are widely commercially available, mirroring the growing popularity of CBD as a supplement for humans. Despite this, experimental evidence of the safety and efficacy of long-term oral exposure in dogs is lacking. The purpose of this study was to address the gap in knowledge around the longer-term suitability and tolerance of a broad-spectrum CBD (THC-free) distillate in clinically healthy dogs. The study was a randomized, placebo-controlled, and blinded study where one group of twenty dogs received daily CBD capsules at a dose of 4 mg/kg of body weight (BW) for a period of 6 months. The control group of twenty dogs received placebo capsules. A comprehensive suite of physiological health measures was performed throughout the study at baseline, and after 2, 4, 10, 18, and 26 weeks of exposure, followed by 4 weeks of washout. CBD concentrations were measured at the same cadence in plasma, feces and urine. Health measures included biochemistry, hematology, urinalysis, in addition to fortnightly veterinary examinations, twice daily well-being observations, and a daily quality-of-life survey. Biochemistry and hematology showed no clinically significant alterations apart from a transient elevation in alkaline phosphatase (ALP) in just over half of the dogs receiving CBD. This elevation was observed in the absence of concurrent elevations of other liver parameters, and without any adverse effects on health and wellbeing. Furthermore, bone alkaline phosphatase (BALP) was simultaneously elevated with a significant, strong (r > 0.9) positive correlation between the two measures, suggesting that the elevation of total ALP was at least partly due to the bone-derived isoform. This study provides evidence that a once-daily oral dose of 4 mg CBD/kg BW is well tolerated in clinically healthy dogs for a duration of 6-months.

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“…6,32,33 Due to estrogen dysregulation, the overactivation of osteoclasts may lead to imbalance of bone resorption and formation during postmenopausal osteoporosis. 34,35 However, the modulatory mechanisms underlying osteoclast differentiation in osteoporosis remain obscure.…”

Section: Discussionmentioning

confidence: 99%

“…Osteoporosis is a common bone disease, caused by environmental pollution, utilization of glucocorticoid, and estrogen dysfunction 6,32,33 . Due to estrogen dysregulation, the overactivation of osteoclasts may lead to imbalance of bone resorption and formation during postmenopausal osteoporosis 34,35 . However, the modulatory mechanisms underlying osteoclast differentiation in osteoporosis remain obscure.…”

Section: Discussionmentioning

confidence: 99%

METTL14 represses osteoclast formation to ameliorate osteoporosis via enhancing GPX4 mRNA stability

Deng

Luo²,

Cao³

et al. 2023

Environmental Toxicology

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Excessive bone resorption by osteoclasts results in the development of multiple bone disorders including osteoporosis. This study aimed to explore the biological function of methyltransferase‐like14 (METTL14) in osteoclast formation, as well as its related mechanisms. Expression levels of METTL14, GPX4 and osteoclast‐related proteins TRAP, NFATc1, c‐Fos were detected by qRT‐PCR and Western blotting. The osteoporosis model was established in mice by bilateral ovariectomy (OVX). Bone histomorphology was determined by micro‐CT and H&E staining. NFATc1 expression in bone tissues was determined by immunohistochemical staining. Proliferation of primary bone marrow macrophages cells (BMMs) was assessed by MTT assay. Osteoclast formation was observed by TRAP staining. The regulatory mechanism was evaluated by RNA methylation quantification assay, MeRIP‐qPCR, dual luciferase reporter assay, and RIP, respectively. METTL14 was down‐regulated in the serum samples of postmenopausal osteoporotic women, which was positively associated with bone mineral density (BMD). Osteoclast formation was promoted in OVX‐treated METTL14+/− mice as compared with wild‐type littermates. Conversely, METTL14 overexpression repressed RANKL‐induced osteoclast differentiation of BMMs. Mechanistically, METTL14‐mediated m6A modification post‐transcriptionally stabilized glutathione peroxidase 4 (GPX4), with the assistance of Hu‐Antigen R (HuR). Finally, GPX4 depletion‐mediated osteoclast formation in BMMs could be counteracted by METTL14 or HuR overexpression. Collectively, METTL14 inhibits osteoclastogenesis and bone resorption via enhancing GPX4 stability through an m6A‐HuR dependent mechanism. Therefore, targeting METTL14 might be a novel promising treatment strategy for osteoporosis.

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Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 MAPK

Cited by 21 publications

References 49 publications

Cannabidiol Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in the Inflammatory Microenvironment via the CB2-dependent p38 MAPK Signaling Pathway

Cannabidiol Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in the Inflammatory Microenvironment via the CB2-dependent p38 MAPK Signaling Pathway

Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs

METTL14 represses osteoclast formation to ameliorate osteoporosis via enhancing GPX4 mRNA stability

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