International Journal of Stem Cells

  • 제15권4호
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  • Pages.405-414
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  • 2022
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  • 2005-3606(pISSN)
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  • 2005-5447(eISSN)
한국줄기세포학회 (Korean Society for Stem Cell Research)
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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

  • Lin Li (Medical School of Chinese PLA) ;
  • Jin Feng (Department of Stomatology, The First Medical Center, Chinese PLA General Hospital) ;
  • Lei Sun (Department of Stomatology, Medical Center of Chinese People's Liberation Army Strategic Support Force) ;
  • Yao-wei Xuan (Medical School of Chinese PLA) ;
  • Li Wen (Department of Stomatology, The First Medical Center, Chinese PLA General Hospital) ;
  • Yun-xia Li (Department of Stomatology, The First Medical Center, Chinese PLA General Hospital) ;
  • Shuo Yang (Department of Stomatology, The First Medical Center, Chinese PLA General Hospital) ;
  • Biao Zhu (Department of Stomatology, Fuxing Hospital, Capital Medical University) ;
  • Xiao-yu Tian (Medical School of Chinese PLA) ;
  • Shuang Li (Department of Stomatology, Fuxing Hospital, Capital Medical University) ;
  • Li-sheng Zhao (Department of Stomatology, The First Medical Center, Chinese PLA General Hospital) ;
  • Rui-jie Dang (Department of Stomatology, The First Medical Center, Chinese PLA General Hospital) ;
  • Ting Jiao (Department of Oncology, Affiliated Hospital of Hebei University, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy) ;
  • Hai-song Zhang (Department of Oncology, Affiliated Hospital of Hebei University, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy) ;
  • Ning Wen (Department of Stomatology, The First Medical Center, Chinese PLA General Hospital)
  • 투고 : 2021.09.07
  • 심사 : 2022.01.04
  • 발행 : 2022.11.30
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초록

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.

키워드

과제정보

This work was supported by grants from Project funded by China Postdoctoral Science Foundation (2019T120980, 2018M633722) and National Natural Science Foundation of China (NSFC51802350, NSFC51972339).

참고문헌

  1. Liu H, Li D, Zhang Y, Li M. Inflammation, mesenchymal stem cells and bone regeneration. Histochem Cell Biol 2018;149:393-404
  2. Redlich K, Smolen J. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov 2012;11:234-250
  3. Zaidi M, Sun L, Blair HC. Special stem cells for bone. Cell Stem Cell 2012;10:233-234
  4. Fierro FA, Nolta JA, Adamopoulos IE. Concise review: stem cells in osteoimmunology. Stem Cells 2017;35:1461-1467
  5. Liu D, Xu J, Liu O, Fan Z, Liu Y, Wang F, Ding G, Wei F, Zhang C, Wang S. Mesenchymal stem cells derived from inflamed periodontal ligaments exhibit impaired immunomodulation. J Clin Periodontol 2012;39:1174-1182
  6. Zaidi M. Skeletal remodeling in health and disease. Nat Med 2007;13:791-801
  7. Izzo A, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009;30:515-527 Erratum in: Trends Pharmacol Sci 2009;30:609
  8. Miranzadeh Mahabadi H, Bhatti H, Laprairie RB, Taghibiglou C. Cannabinoid receptors distribution in mouse cortical plasma membrane compartments. Mol Brain 2021;14:89
  9. Kozela E, Juknat A, Gao F, Kaushansky N, Coppola G, Vogel Z. Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells. J Neuroinflammation 2016;13:136
  10. Couch D, Tasker C, Theophilidou E, Lund J, O'Sullivan S. Cannabidiol and palmitoylethanolamide are anti-inflammatory in the acutely inflamed human colon. Clin Sci (Lond) 2017;131:2611-2626
  11. Huang Y, Wan T, Pang N, Zhou Y, Jiang X, Li B, Gu Y, Huang Y, Ye X, Lian H, Zhang Z, Yang L. Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway. J Cell Physiol 2019;234:21224-21234
  12. Jastrzab A, Gegotek A, Skrzydlewska E. Cannabidiol regulates the expression of keratinocyte proteins involved in the inflammation process through transcriptional regulation. Cells 2019;8:827
  13. Philpott H, O'Brien M, McDougall J. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain 2017;158:2442-2451
  14. Verrico C, Wesson S, Konduri V, Hofferek C, Vazquez-Perez J, Blair E, Dunner K Jr, Salimpour P, Decker WK, Halpert MM. A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Pain 2020;161:2191-2202
  15. Apostu D, Lucaciu O, Mester A, Benea H, Oltean-Dan D, Onisor F, Baciut M, Bran S. Cannabinoids and bone regeneration. Drug Metab Rev 2019;51:65-75
  16. Saint-Pastou Terrier C, Gasque P. Bone responses in health and infectious diseases: a focus on osteoblasts. J Infect 2017;75:281-292
  17. Yang Y, Dong X, Ma W, Guan L, Wang YH, Huang XH, Chen JF, Zhao X. Proliferation, differentiation and immunoregulatory capacities of brown and white adipose-derived stem cells from young and aged mice. Int J Stem Cells 2020;13:246-256
  18. Yang S, Zhu B, Yin P, Zhao L, Wang Y, Fu Z, Dang R, Xu J, Zhang J, Wen N. Integration of human umbilical cord mesenchymal stem cells-derived exosomes with hydroxyapatite-embedded hyaluronic acid-alginate hydrogel for bone regeneration. ACS Biomater Sci Eng 2020;6:1590-1602
  19. Libro R, Scionti D, Diomede F, Marchisio M, Grassi G, Pollastro F, Piattelli A, Bramanti P, Mazzon E, Trubiani O. Cannabidiol modulates the immunophenotype and inhibits the activation of the inflammasome in human gingival mesenchymal stem cells. Front Physiol 2016;7:559
  20. Yu X, Quan J, Long W, Chen H, Wang R, Guo J, Lin X, Mai S. LL-37 inhibits LPS-induced inflammation and stimulates the osteogenic differentiation of BMSCs via P2X7 receptor and MAPK signaling pathway. Exp Cell Res 2018;372:178-187
  21. Qian H, Zhao Y, Peng Y, Han C, Li S, Huo N, Ding Y, Duan Y, Xiong L, Sang H. Activation of cannabinoid receptor CB2 regulates osteogenic and osteoclastogenic gene expression in human periodontal ligament cells. J Periodontal Res 2010;45:504-511
  22. Bab I, Zimmer A. Cannabinoid receptors and the regulation of bone mass. Br JPharmacol 2008;153:182-188
  23. Idris A, van't Hof R, Greig I, Ridge S, Baker D, Ross R, Ralston SH. Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors. Nat Med 2005;11:774-779
  24. Gibon E, Lu L, Goodman SB. Aging, inflammation, stem cells, and bone healing. Stem Cell Res Ther 2016;7:44
  25. Britch S, Babalonis S, Walsh S. Cannabidiol: pharmacology and therapeutic targets. Psychopharmacology (Berl) 2021;238:9-28
  26. Schmuhl E, Ramer R, Salamon A, Peters K, Hinz B. Increase of mesenchymal stem cell migration by cannabidiol via activation of p42/44 MAPK. Biochem Pharmacol 2014;87:489-501
  27. Qi X, Liu C, Li G, Luan H, Li S, Yang D, Zhou Z. Investigation of in vitro odonto/osteogenic capacity of cannabidiol on human dental pulp cell. J Dent 2021;109:103673
  28. Kamali A, Oryan A, Hosseini S, Ghanian MH, Alizadeh M, Baghaban Eslaminejad M, Baharvand H. Cannabidiol-loaded microspheres incorporated into osteoconductive scaffold enhance mesenchymal stem cell recruitment and regeneration of critical-sized bone defects. Mater Sci Eng C Mater Biol Appl 2019;101:64-75 Erratum in: Mater Sci Eng C Mater Biol Appl 2021;126:112179
  29. Idris A, Sophocleous A, Landao-Bassonga E, van't Hof R, Ralston S. Regulation of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type 2 cannabinoid receptor. Endocrinology 2008;149:5619-5626
  30. Scutt A, Williamson EM. Cannabinoids stimulate fibroblastic colony formation by bone marrow cells indirectly via CB2 receptors. Calcif Tissue Int 2007;80:50-59
  31. Wang J, Lu HX, Wang J. Cannabinoid receptors in osteoporosis and osteoporotic pain: a narrative update of review. J Pharm Pharmacol 2019;71:1469-1474
  32. Yan W, Cao Y, Yang H, Han N, Zhu X, Fan Z, Du J, Zhang F. CB1 enhanced the osteo/dentinogenic differentiation ability of periodontal ligament stem cells via p38 MAPK and JNK in an inflammatory environment. Cell Prolif 2019;52:e12691
  33. Navarro G, Reyes-Resina I, Rivas-Santisteban R, Sanchez de Medina V, Morales P, Casano S, Ferreiro-Vera C, Lillo A, Aguinaga D, Jagerovic N, Nadal X, Franco R. Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 hetero-receptor complexes. Biochem Pharmacol 2018;157:148-158
  34. Kang M, Lee J, Park S. Cannabidiol induces osteoblast differentiation via angiopoietin1 and p38 MAPK. Environ Toxicol 2020;35:1318-1325
  35. Rahaman O, Ganguly D. Endocannabinoids in immune regulation and immunopathologies. Immunology 2021;164:242-252
  36. Wang B, LianK, Li J, Mei G. Restoration of osteogenic differentiation by overexpression of cannabinoid receptor 2 in bone marrow mesenchymal stem cells isolated from osteoporotic patients. Exp Ther Med 2018;15:357-364
  37. Ge C, Yang Q, Zhao G, Yu H, Kirkwood KL, Franceschi RT. Interactions between extracellular signal-regulated kinase 1/2 and P38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity. J Bone Miner Res 2021;36:2096-2097 Erratum in: J Bone Miner Res 2012;27:538-551
  38. Whyte L, Ryberg E, Sims N, Ridge S, Mackie K, Greasley P, Ross RA, Rogers MJ.The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 2009;106:16511-16516