Open Access

Berberine improves advanced glycation end products‑induced osteogenic differentiation responses in human periodontal ligament stem cells through the canonical Wnt/β‑catenin pathway

  • Authors:
    • Li‑Na Zhang
    • Xu‑Xia Wang
    • Zhi Wang
    • Ke‑Yi Li
    • Bao‑Hua Xu
    • Jun Zhang
  • View Affiliations

  • Published online on: April 25, 2019     https://doi.org/10.3892/mmr.2019.10193
  • Pages: 5440-5452
  • Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The aim of the present study was to investigate the effects of advanced glycation end products (AGEs) and berberine hydrochloride (BBR) on the osteogenic differentiation ability of human periodontal ligament stem cells (hPDLSCs) in vitro, and their underlying mechanisms. hPDLSCs were subjected to osteogenic induction and were treated with AGEs or AGEs + BBR. Following varying numbers of days in culture, alkaline phosphatase (ALP) activity assays, ALP staining, alizarin red staining, ELISAs, and reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analyses were performed to determine the osteogenic differentiation ability of hPDLSCs; RT‑qPCR, western blot analysis, and immunofluorescence staining were conducted to investigate the underlying mechanisms. The canonical Wnt/β‑catenin pathway inhibitor XAV‑939 and agonist CHIR‑99021 were used to determine the contribution of the canonical Wnt/β‑catenin pathway to differentiation. Treatment with AGEs resulted in reduced ALP activity and Collagen I protein levels, decreased ALP staining, fewer mineralized nodules, and downregulated expression of osteogenic‑specific genes [Runt‑related transcription factor 2 (Runx2), Osterix, ALP, osteopontin (OPN), Collagen I and osteocalcin (OCN)] and proteins (Runx2, OPN, BSP and OCN); however, BBR partially rescued the AGE‑induced decrease in the osteogenic potential of hPDLSCs. Furthermore, AGEs activated the canonical Wnt/β‑catenin signaling pathway and promoted the nuclear translocation of β‑catenin; BBR partially attenuated this effect. In addition, XAV‑939 partially rescued the AGE‑induced reduction in the osteogenic potential of hPDLSCs, whereas CHIR‑99021 suppressed the BBR‑induced increase in the osteogenic potential of hPDLSCs. The present study indicated that AGEs attenuated the osteogenic differentiation ability of hPDLSCs, in part by activating the canonical Wnt/β‑catenin pathway; however, BBR attenuated these effects by inhibiting the canonical Wnt/β‑catenin pathway. These findings suggest a role for BBR in periodontal regeneration induced by hPDLSCs in patients with diabetes mellitus.

References

1 

Preshaw PM, Alba AL, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K and Taylor R: Periodontitis and diabetes: A two-way relationship. Diabetologia. 55:21–31. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Löe H: Periodontal disease. The sixth complication of diabetes mellitus. Diabetes Care. 16:329–334. 1993. View Article : Google Scholar : PubMed/NCBI

3 

Liu N, Shi S, Deng M, Tang L, Zhang G, Liu N, Ding B, Liu W, Liu Y, Shi H, et al: High levels of β-catenin signaling reduce osteogenic differentiation of stem cells in inflammatory microenvironments through inhibition of the noncanonical Wnt pathway. J Bone Miner Res. 26:2082–2095. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Poulsen MW, Hedegaard RV, Andersen JM, de Courten B, Bügel S, Nielsen J, Skibsted LH and Dragsted LO: Advanced glycation endproducts in food and their effects on health. Food Chem Toxicol. 60:10–37. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Gurav AN: Advanced glycation end products: A link between periodontitis and diabetes mellitus? Curr Diabetes Rev. 9:355–361. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Zizzi A, Tirabassi G, Aspriello SD, Piemontese M, Rubini C and Lucarini G: Gingival advanced glycation end-products in diabetes mellitus-associated chronic periodontitis: An immunohistochemical study. J Periodontal Res. 48:293–301. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Bosshardt DD and Sculean A: Does periodontal tissue regeneration really work? Periodontol 2000. 51:208–219. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Reynolds MA, Kao RT, Camargo PM, Caton JG, Clem DS, Fiorellini JP, Geisinger ML, Mills MP, Nares S and Nevins ML: Periodontal regeneration-intrabony defects: A consensus report from the AAP Regeneration Workshop. J Periodontol 86 (2 Suppl). S105–S107. 2015. View Article : Google Scholar

9 

Bartold PM, Gronthos S, Ivanovski S, Fisher A and Hutmacher DW: Tissue engineered periodontal products. J Periodontal Res. 51:1–15. 2016. View Article : Google Scholar : PubMed/NCBI

10 

Cai C, Yuan GJ, Huang Y, Yang N, Chen X, Wen L, Wang X, Zhang L and Ding Y: Estrogen-related receptor α is involved in the osteogenic differentiation of mesenchymal stem cells isolated from human periodontal ligaments. Int J Mol Med. 31:1195–1201. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Drake MT, Clarke BL and Khosla S: Bisphosphonates: Mechanism of action and role in clinical practice. Mayo Clin Proc. 83:1032–1045. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Kuo YJ, Tsuang FY, Sun JS, Lin CH, Chen CH, Li JY, Huang YC, Chen WY, Yeh CB and Shyu JF: Calcitonin inhibits SDCP-induced osteoclast apoptosis and increases its efficacy in a rat model of osteoporosis. PLoS One. 7:e402722012. View Article : Google Scholar : PubMed/NCBI

13 

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, et al: Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 10:1344–1351. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA and Lewis K: Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA. 97:1433–1437. 2000. View Article : Google Scholar : PubMed/NCBI

15 

Yang J, Yin J, Gao H, Xu L, Wang Y, Xu L and Li M: Berberine improves insulin sensitivity by inhibiting fat store and adjusting adipokines profile in human preadipocytes and metabolic syndrome patients. Evid Based Complement Alternat Med. 2012:3638452012. View Article : Google Scholar : PubMed/NCBI

16 

Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Reya T and Clevers H: Wnt signalling in stem cells and cancer. Nature. 434:843–850. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Krishnan V, Bryant HU and Macdougald OA: Regulation of bone mass by Wnt signaling. J Clin Invest. 116:1202–1209. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, Deng L, Clemens TL and Williams BO: Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 280:21162–21168. 2005. View Article : Google Scholar : PubMed/NCBI

20 

Miller JR: The Wnts. Genome Biol. 3:REVIEWS30012002.PubMed/NCBI

21 

Rawadi G, Vayssière B, Dunn F, Baron R and Roman-Roman S: BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J Bone Miner Res. 18:1842–1853. 2003. View Article : Google Scholar : PubMed/NCBI

22 

de Boer J, Siddappa R, Gaspar C, van Apeldoorn A, Fodde R and van Blitterswijk C: Wnt signaling inhibits osteogenic differentiation of human mesenchymal stem cells. Bone. 34:818–826. 2004. View Article : Google Scholar : PubMed/NCBI

23 

Boland GM, Perkins G, Hall DJ and Tuan RS: Wnt 3a promotes proliferation and suppresses osteogenic differentiation of adult human mesenchymal stem cells. J Cell Biochem. 93:1210–1230. 2004. View Article : Google Scholar : PubMed/NCBI

24 

van der Horst G, van der Werf SM, Farih-Sips H, van Bezooijen RL, Löwik CW and Karperien M: Downregulation of Wnt signaling by increased expression of Dickkopf-1 and −2 is a prerequisite for late-stage osteoblast differentiation of KS483 cells. J Bone Miner Res. 20:1867–1877. 2005. View Article : Google Scholar : PubMed/NCBI

25 

Wang M, Zhang W, Xu S, Peng L, Wang Z, Liu H, Fang Q, Deng T, Men X and Lou J: TRB3 mediates advanced glycation end product-induced apoptosis of pancreatic β-cells through the protein kinase C β pathway. Int J Mol Med. 40:130–136. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Zhang H, Shan Y, Wu Y, Xu C, Yu X, Zhao J, Yan J and Shang W: Berberine suppresses LPS-induced inflammation through modulating Sirt1/NF-κB signaling pathway in RAW264.7 cells. Int Immunopharmacol. 52:93–100. 2017. View Article : Google Scholar : PubMed/NCBI

27 

Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD and MacDougald OA: Regulation of Wnt signaling during adipogenesis. J Biol Chem. 277:30998–31004. 2002. View Article : Google Scholar : PubMed/NCBI

28 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

29 

Liccardo D, Cannavo A, Spagnuolo G, Ferrara N, Cittadini A, Rengo C and Rengo G: Periodontal disease: A risk factor for diabetes and cardiovascular disease. Int J Mol Sci. 20(pii): E14142019. View Article : Google Scholar : PubMed/NCBI

30 

Gheorghita D, Eördegh G, Nagy F and Antal M: Periodontal disease, a risk factor for atherosclerotic cardiovascular disease. Orv Hetil. 160:419–425. 2019.(In Hungarian). View Article : Google Scholar : PubMed/NCBI

31 

Du J, Shan Z, Ma P, Wang S and Fan Z: Allogeneic bone marrow mesenchymal stem cell transplantation for periodontal regeneration. J Dent Res. 93:183–188. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Chamila Prageeth Pandula PK, Samaranayake LP, Jin LJ and Zhang C: Periodontal ligament stem cells: An update and perspectives. J Investig Clin Dent. 5:81–90. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Trubiani O, Di Primio R, Traini T, Pizzicannella J, Scarano A, Piattelli A and Caputi S: Morphological and cytofluorimetric analysis of adult mesenchymal stem cells expanded ex vivo from periodontal ligament. Int J Immunopathol Pharmacol. 18:213–221. 2005. View Article : Google Scholar : PubMed/NCBI

34 

Morsczeck C and Reichert TE: Dental stem cells in tooth regeneration and repair in the future. Expert Opin Biol Ther. 18:187–196. 2018. View Article : Google Scholar : PubMed/NCBI

35 

An K and Liu H: Survival of bone marrow mesenchymal stem cells and periodontal ligament stem cells in cell sheets. Zhonghua Kou Qiang Yi Xue Za Zhi. 49:682–687. 2014.(In Chinese). PubMed/NCBI

36 

Yao S, Zhao W, Ou Q, Liang L, Lin X and Wang Y: MicroRNA-214 suppresses osteogenic differentiation of human periodontal ligament stem cells by targeting ATF4. Stem Cells Int. 2017:30286472017. View Article : Google Scholar : PubMed/NCBI

37 

Ji K, Liu Y, Lu W, Yang F, Yu J, Wang X, Ma Q, Yang Z, Wen L and Xuan K: Periodontal tissue engineering with stem cells from the periodontal ligament of human retained deciduous teeth. J Periodontal Res. 48:105–116. 2013. View Article : Google Scholar : PubMed/NCBI

38 

Borgnakke WS, Ylöstalo PV, Taylor GW and Genco RJ: Effect of periodontal disease on diabetes: Systematic review of epidemiologic observational evidence. J Clin Periodontol. 40 (Suppl 14):S135–S152. 2013. View Article : Google Scholar : PubMed/NCBI

39 

Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, Offenbacher S, Ridker PM, Van Dyke TE, Roberts WC, et al: The American journal of cardiology and journal of periodontology editors' consensus: Periodontitis and atherosclerotic cardiovascular disease. Am J Cardiol. 104:59–68. 2009. View Article : Google Scholar : PubMed/NCBI

40 

Vlassara H and Uribarri J: Advanced glycation end products (AGE) and diabetes: Cause, effect, or both? Curr Diab Rep. 14:4532014. View Article : Google Scholar : PubMed/NCBI

41 

Liu D, Xu J, Liu O, Fan Z, Liu Y, Wang F, Ding G, Wei F, Zhang C and Wang S: Mesenchymal stem cells derived from inflamed periodontal ligaments exhibit impaired immunomodulation. J Clin Periodontol. 39:1174–1182. 2012. View Article : Google Scholar : PubMed/NCBI

42 

Liu Q, Hu CH, Zhou CH, Cui XX, Yang K, Deng C, Xia JJ, Wu Y, Liu LC and Jin Y: DKK1 rescues osteogenic differentiation of mesenchymal stem cells isolated from periodontal ligaments of patients with diabetes mellitus induced periodontitis. Sci Rep. 5:131422015. View Article : Google Scholar : PubMed/NCBI

43 

Kume S, Kato S, Yamagishi S, Inagaki Y, Ueda S, Arima N, Okawa T, Kojiro M and Nagata K: Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J Bone Miner Res. 20:1647–1658. 2005. View Article : Google Scholar : PubMed/NCBI

44 

Pandey MK, Sung B, Kunnumakkara AB, Sethi G, Chaturvedi MM and Aggarwal BB: Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res. 68:5370–5379. 2008. View Article : Google Scholar : PubMed/NCBI

45 

Singh T, Vaid M, Katiyar N, Sharma S and Katiyar SK: Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors. Carcinogenesis. 32:86–92. 2011. View Article : Google Scholar : PubMed/NCBI

46 

Hu JP, Nishishita K, Sakai E, Yoshida H, Kato Y, Tsukuba T and Okamoto K: Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways. Eur J Pharmacol. 580:70–79. 2008. View Article : Google Scholar : PubMed/NCBI

47 

Yang W and Ma B: A mini-review: The therapeutic potential of mesenchymal stem cells and relevant signaling factors. Curr Stem Cell Res Ther. Sep 12–2018.(Epub ahead of print). doi: 10.2174/1574888X13666180912141228.

48 

Moon RT, Kohn AD, De Ferrari GV and Kaykas A: WNT and beta-catenin signalling: Diseases and therapies. Nat Rev Genet. 5:691–701. 2004. View Article : Google Scholar : PubMed/NCBI

49 

Aberle H, Bauer A, Stappert J, Kispert A and Kemler R: beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J. 16:3797–3804. 1997. View Article : Google Scholar : PubMed/NCBI

50 

Lee HW, Suh JH, Kim HN, Kim AY, Park SY, Shin CS, Choi JY and Kim JB: Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J Bone Miner Res. 23:1227–1237. 2008. View Article : Google Scholar : PubMed/NCBI

51 

Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, et al: Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 461:614–620. 2009. View Article : Google Scholar : PubMed/NCBI

52 

Bulut-Karslioglu A, Biechele S, Jin H, Macrae TA, Hejna M, Gertsenstein M, Song JS and Ramalho-Santos M: Inhibition of mTOR induces a paused pluripotent state. Nature. 540:119–123. 2016. View Article : Google Scholar : PubMed/NCBI

53 

Han J, Wu Q, Xia Y, Wagner MB and Xu C: Cell alignment induced by anisotropic electrospun fibrous scaffolds alone has limited effect on cardiomyocyte maturation. Stem Cell Res. 16:740–750. 2016. View Article : Google Scholar : PubMed/NCBI

54 

Staines KA, MacRae VE and Farquharson C: The importance of the SIBLING family of proteins on skeletal mineralisation and bone remodelling. J Endocrinol. 214:241–255. 2012. View Article : Google Scholar : PubMed/NCBI

55 

Neve A, Corrado A and Cantatore FP: Osteocalcin: Skeletal and extra-skeletal effects. J Cell Physiol. 228:1149–1153. 2013. View Article : Google Scholar : PubMed/NCBI

56 

Kruger TE, Miller AH, Godwin AK and Wang J: Bone sialoprotein and osteopontin in bone metastasis of osteotropic cancers. Crit Rev Oncol Hematol. 89:330–341. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 19 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhang, L., Wang, X., Wang, Z., Li, K., Xu, B., & Zhang, J. (2019). Berberine improves advanced glycation end products‑induced osteogenic differentiation responses in human periodontal ligament stem cells through the canonical Wnt/β‑catenin pathway. Molecular Medicine Reports, 19, 5440-5452. https://doi.org/10.3892/mmr.2019.10193
MLA
Zhang, L., Wang, X., Wang, Z., Li, K., Xu, B., Zhang, J."Berberine improves advanced glycation end products‑induced osteogenic differentiation responses in human periodontal ligament stem cells through the canonical Wnt/β‑catenin pathway". Molecular Medicine Reports 19.6 (2019): 5440-5452.
Chicago
Zhang, L., Wang, X., Wang, Z., Li, K., Xu, B., Zhang, J."Berberine improves advanced glycation end products‑induced osteogenic differentiation responses in human periodontal ligament stem cells through the canonical Wnt/β‑catenin pathway". Molecular Medicine Reports 19, no. 6 (2019): 5440-5452. https://doi.org/10.3892/mmr.2019.10193