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Cannabidiol Promotes Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in the Inflammatory Microenvironment via the CB2-dependent p38 MAPK Signaling Pathway
International Journal of Stem Cells
Published online February 28, 2022;  
© 2022 Korean Society for Stem Cell Research.

Lin Li1,*, Jin Feng2,*, Lei Sun3, Yao-wei Xuan1, Li Wen2, Yun-xia Li2, Shuo Yang2, Biao Zhu4, Xiao-yu Tian1, Shuang Li4, Li-sheng Zhao2, Rui-jie Dang2, Ting Jiao5, Hai-song Zhang5, Ning Wen2

1Medical School of Chinese PLA, Beijing, China
2Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
3Department of Stomatology, Medical Center of Chinese People’s Liberation Army Strategic Support Force, Beijing, China
4Department of Stomatology, Fuxing Hospital, Capital Medical University, Beijing, China
5Department of Oncology, Affiliated Hospital of Hebei University, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Baoding, China
Correspondence to: Ning Wen
Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Fuxing Road 28, Beijing 100853, China
Tel: +86-010-66937947, Fax: +86-010-66937947, E-mail: wenningchn@163.com
Co-Correspondence to Ting Jiao
Department of Oncology, Affiliated Hospital of Hebei University, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Yuhua Dong Road 212, Baoding 071000, China
Tel: +86-189-0336-3309, Fax: +86-0312-5983032, E-mail: tingjiao0504@126.com
*These authors contributed equally to this work.
Received September 7, 2021; Revised November 29, 2021; Accepted January 4, 2022.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
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.
Keywords : Cannabidiol (CBD), Osteogenic differentiation, Inflammatory microenvironment, Cannabinoid receptor 2 (CB2), p38 MAPK signaling pathway