SpringerLink
Log in

Chondroitin Sulfate Enhances Proliferation and Migration via Inducing β-Catenin and Intracellular ROS as Well as Suppressing Metalloproteinases through Akt/NF-ϰB Pathway Inhibition in Human Chondrocytes

  • Original Research
  • Published:
The journal of nutrition, health & aging

Abstract

Background

Chondroitin sulfate (CS) is found in humans’ cartilage, bone, cornea, skin, and arterial wall. It consists of the foundation substance in the extracellular matrix (ECM) of connective tissue. The oral supplement form of CS is clinically used in treating osteoarthritis (OA).

Methods

Cell migration was observed by the transwell assay. The EMT, Akt/IKK/IϰB pathways, TIMPs, collagen and MMPs in cell lysate were determined by Western blotting. The expression of MMP activity was determined by gelatin zymography. The production of reactive oxygen species (ROS) was determined by using a fluorescence spectrophotometer.

Results

In the current report, we demonstrated that CS can increase the cell proliferation and migration of chon-001 chondrocytes. Treatment with CS induced the epithelial—mesenchymal transition and increased the expression of type II collagen and TIMP-1/TIMP2 and inhibited the expressions and activities of metalloproteinase-9 (MMP-9) and metalloproteinase-2 (MMP-2). The phosphorylation of Akt, IϰB kinase (IKK), IϰB and p65 was decreased by CS. CS treatment resulted in β-catenin production and XAV939, a β-catenin inhibitor, and inhibited the cell proliferation by CS treatment. In addition, also significantly induced intracellular ROS generation. Treatment with antioxidant propyl gallate blocked cell migration induced by CS.

Conclusion

We demonstrated that CS induced cell proliferation and migration of chondrocytes by inducing β-catenin and enhancing ROS production. Moreover, our studies demonstrated that CS can increase the activity of chondrocytes and help patients with osteoarthritis to restore cartilage function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Deal CL, Moskowitz RW. Nutraceuticals as therapeutic agents in osteoarthritis: the role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheumatic Disease Clinics of North America 1999;5: 379–95. https://doi.org/10.1016/S0889-857X(05)70074-0

    Article  Google Scholar 

  2. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. Jama 2000;283: 1469–75. https://doi.org/10.1001/jama.283.11.1469

    Article  CAS  Google Scholar 

  3. Al Faqeh H, Hamdan BMYN, Chen HC, Aminuddin BS, Ruszymah BHI. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Experimental gerontology 2012;47: 458–64. https://doi.org/10.1016/j.exger.2012.03.018

    Article  Google Scholar 

  4. Jiang Y, Tuan RS. Origin and function of cartilage stem/progenitor cells in osteoarthritis. Nature Reviews Rheumatology 2015;11: 206. https://doi.org/10.1038/nrrheum.2014.200

    Article  Google Scholar 

  5. Zhang X, Yao J, Wu Z, Zou K, Yang Z, Huang X, Luan Z, Li J, Wei Q. Chondroprotective and antiarthritic effects of Daphnetin used in vitro and in vivo osteoarthritis models. Life sciences 2020;240: 116857. https://doi.org/10.1016/j.lfs.2019.116857

    Article  CAS  Google Scholar 

  6. Volpi N. Chondroitin sulfate safety and quality. Molecules 2019;24: 14473 https://doi.org/10.3390/molecules24081447

    Article  Google Scholar 

  7. Lamari FN. The potential of chondroitin sulfate as a therapeutic agent. Connective tissue research 2008;49: 289–92. https://doi.org/10.1080/03008200802148314

    Article  CAS  Google Scholar 

  8. Toida T, Sakai S, Akiyama H, Linhardt RJ. Immunological activity of chondroitin sulfate. Advances in Pharmacology 2006;53: 403–15. https://doi.org/10.1016/S1054-3589(05)53019-9

    Article  CAS  Google Scholar 

  9. Nandini CD, Sugahara K. Role of the sulfation pattern of chondroitin sulfate in its biological activities and in the binding of growth factors. Advances in pharmacology 2006;53: 253–79. https://doi.org/10.1016/S1054-3589(05)53012-6

    Article  CAS  Google Scholar 

  10. Murphy G. Tissue inhibitors of metalloproteinases. Genome biology 2011;12: 233. https://doi.org/10.1186/gb-2011-12-11-233

    Article  CAS  Google Scholar 

  11. Hung C-Y, Lee C-H, Chiou H-L, Lin C-L, Chen P-N, Lin M-T, Hsieh Y-H, Chou M-C. Praeruptorin-b inhibits 12-o-tetradecanoylphorbol-13-acetate-induced cell invasion by targeting akt/nf-kappab via matrix metalloproteinase-2/-9 expression in human cervical cancer cells. Cell Physiol Biochem 2019;52: 1255–66. https://doi.org/10.33594/000000088

    Article  Google Scholar 

  12. Li X, Peng J, Wu M, Ye H, Zheng C, Wu G, Xu H, Chen X, Liu X. BMP2 promotes chondrocyte proliferation via the Wnt/β-catenin signaling pathway. Molecular medicine reports 2011;: 621–6. https://doi.org/10.1111/iwj.12557

  13. Dunnill C, Patton T, Brennan J, Barrett J, Dryden M, Cooke J, Leaper D, Georgopoulos NT. Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process. International wound journal 2017;14: 89–96. https://doi.org/10.1111/iwj.12557

    Article  Google Scholar 

  14. Kember N, Walker K. Control of bone growth in rats. Nature 1971;229: 428–9. https://doi.org/10.1038/229428a0

    Article  CAS  Google Scholar 

  15. Zhou S, Shen Y, Wang L, Li P. Epithelial-mesenchymal transition and mesenchymalepithelial transition response during differentiation of growth-plate chondrocytes in endochondral ossification. International journal of clinical and experimental medicine 2015;8: 12076. PMID: 26550119

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sun S-C. The non-canonical NF-ϰB pathway in immunity and inflammation. Nature Reviews Immunology 2017;17: 545. https://doi.org/10.1038/nri.2017.52

    Article  CAS  Google Scholar 

  17. Bond M, Chase AJ, Baker AH, Newby AC. Inhibition of transcription factor NF-ϰB reduces matrix metalloproteinase-1,-3 and-9 production by vascular smooth muscle cells. Cardiovascular research 2001;50: 556–65. https://doi.org/10.1016/S0008-6363(01)00220-6

    Article  CAS  Google Scholar 

  18. Ahmad A, Biersack B, Li Y, Kong D, Bao B, Schobert R, B Padhye S, H Sarkar F. Targeted regulation of PI3K/Akt/mTOR/NF-ϰB signaling by indole compounds and their derivatives: mechanistic details and biological implications for cancer therapy. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 2013;13: 1002–13. https://doi.org/10.2174/18715206113139990078

    CAS  Google Scholar 

  19. Clancy R, Gomez P, Abramson S. Nitric oxide sustains nuclear factor kappaB activation in cytokine-stimulated chondrocytes. Osteoarthritis and Cartilage 2004;12: 552–8. https://doi.org/10.1016/j.joca.2004.04.003

    Article  CAS  Google Scholar 

  20. Wang P, Meng Q, Wang W, Zhang S, **ong X, Qin S, Zhang J, Li A, Liu Z. Icariin inhibits the inflammation through down-regulating NF-KB/HLF-2ct signal pathways in chondrocytes. Bioscience Reports 2020;40. https://doi.org/10.1016/j.lfs.2019.116857

  21. Henrotin Y, Kurz B. Antioxidant to treat osteoarthritis: dream or reality? Current drug targets 2007;8: 347–57. https://doi.org/10.2174/138945007779940151

    Article  CAS  Google Scholar 

  22. Kim KS, Choi HW, Yoon HE, Kim IY. Reactive oxygen species generated by NADPH oxidase 2 and 4 are required for chondrogenic differentiation. Journal of Biological Chemistry 2010;285: 40294–302. https://doi.org/10.1074/jbc.M110.126821

    Article  CAS  Google Scholar 

  23. Bai Y, Gong X, Dou C, Cao Z, Dong S. Redox control of chondrocyte differentiation and chondrogenesis. Free Radical Biology and Medicine 2019;132: 83–9. https://doi.org/10.1016/j.freeradbiomed.2018.10.443

    Article  CAS  Google Scholar 

  24. Dao DY, Jonason JH, Zhang Y, Hsu W, Chen D, Hilton MJ, O’Keefe RJ. Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. Journal of Bone and Mineral Research 2012;27: 1680–94. https://doi.org/10.1002/jbmr.1639

    Article  CAS  Google Scholar 

  25. Ma Y, Zheng W, Chen H, Shao X, Lin P, Liu X, Li X, Ye H. Glucosamine promotes chondrocyte proliferation via the Wnt/β-catenin signaling pathway. International journal of molecular medicine 2018;42: 61–70. https://doi.org/10.3892/ijmm.2018.3587

    PubMed  PubMed Central  Google Scholar 

  26. Geborek P, Saxne T, Heinegård D, Wollheim F. Measurement of synovial fluid volume using albumin dilution upon intraarticular saline injection. The Journal of rheumatology 1988;15: 91–4. PMID: 3280796

    CAS  PubMed  Google Scholar 

  27. Rivera F, Bertignone L, Grandi G, Camisassa R, Comaschi G, Trentini D, Zanone M, Teppex G, Vasario G, Fortina G. Effectiveness of intra-articular injections of sodium hyaluronate-chondroitin sulfate in knee osteoarthritis: a multicenter prospective study. Journal of Orthopaedics and Traumatology 2016;17: 27–33. https://doi.org/10.1007/s10195-015-0390-7

    Article  Google Scholar 

Download references

Funding

Funding: Funding for the work was supported by the Chang Gung Memorial Hospital Research Project Grant, Taiwan [grant numbers CMRPG6J0411; CMRPG670261; CMRPG690482].

Author information

Author notes

  1. These authors contributed equally as first author.

Authors and Affiliations

  1. Department of Medicine, Collage of Medicine, Chang Gung University, Taoyuan, Taiwan

    H.-C. Hsu & C.-H. Lin

  2. Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Chia-Yi, Taiwan

    H.-C. Hsu, Y.-L. Ke, Y.-H. Lai, W.-C. Hsieh, C.-H. Lin, S.-S. Huang & J.-Y. Peng

  3. Department of Physical Medicine and Rehabilitation, **amen Chang Gung Hospital, **amen, China

    H.-C. Hsu

  4. Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi City, 60004, Taiwan, ROC

    Ching-Hsein Chen

Authors
  1. H.-C. Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y.-L. Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y.-H. Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W.-C. Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C.-H. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S.-S. Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J.-Y. Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ching-Hsein Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ching-Hsein Chen.

Ethics declarations

The experiments in this study comply with the current laws of the country in which they were perform.

Additional information

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hsu, HC., Ke, YL., Lai, YH. et al. Chondroitin Sulfate Enhances Proliferation and Migration via Inducing β-Catenin and Intracellular ROS as Well as Suppressing Metalloproteinases through Akt/NF-ϰB Pathway Inhibition in Human Chondrocytes. J Nutr Health Aging 26, 307–313 (2022). https://doi.org/10.1007/s12603-022-1752-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12603-022-1752-5

Key words

Search

Navigation