Skip to main content

Advertisement

SpringerLink
Log in

Attenuation of experimental osteoarthritis with human adipose-derived mesenchymal stem cell therapy: inhibition of the pyroptosis in chondrocytes

  • Original Research
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Aim

To explore the role and mechanism of human adipose-derived mesenchymal stem cells (hAD-MSCs) in the treatment of osteoarthritis (OA).

Methods

OA hulth model of Sprague Dawley (SD) rats and 20 ng/ml TNF-α treated chondrocytes were used as models of OA in vivo and in vitro, respectively. hAD-MSCs were administrated in the articular cavity by injection in vivo and co-cultured with chondrocytes using transwell in vitro. Haematoxylin and eosin staining and Safranin-O/Fast green staining were performed to detect tissue destruction and histopathology. Scanning electron microscopy and transmission electron microscopy were used to observe the ultrastructure of chondrocytes. The pyroptosis signaling pathway-related proteins were detected by immunohistochemistry, immunofluorescence, qRT-PCR and Western blot. And small interference technology was used to study the mechanism in depth.

Results

hAD-MSCs could delay the development of rat OA, improve the pathological changes of joints, inhibit the expression of NLRP3, Caspase1, GSDMD and TNFR1. In vitro, the expression of pyroptosis signal proteins in chondrocytes was significantly elevated when stimulated with TNF-α, the level of inflammatory factors such as IL-1β, IL-18 was increased, and the cell morphology was significantly destroyed. While co-cultured with hAD-MSCs, these syndromes were reversed. Knockout of TNFR1 also returned the upregulation of pyroptosis signals which caused by TNF-α.

Conclusion

These results demonstrated that hAD-MSCs could inhibit pyroptosis signaling pathway of chondrocytes induced by TNF-α, which have raised our understanding of the role of hAD-MSCs as promising therapy for the management of OA.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. O'neill TW, Felson DT. Mechanisms of osteoarthritis (OA) pain. Curr Osteoporos Rep. 2018;16(5):611–616.

  2. Palazzo C, Nguyen C, Lefevre-Colau MM, et al. Risk factors and burden of osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):134–8.

    Article  Google Scholar 

  3. Mehana EE, Khafaga AF, El-Blehi SS. The role of matrix metalloproteinases in osteoarthritis pathogenesis: an updated review. Life Sci. 2019;234: 116786.

    Article  CAS  Google Scholar 

  4. Zhang W, Ouyang H, Dass CR, et al. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Res. 2016;4:15040.

    Article  CAS  Google Scholar 

  5. Choi MC, Jo J, Park J, et al. NF-κB signaling pathways in osteoarthritic cartilage destruction. Cells, 2019,8(7).

  6. Peng Z, Sun H, Bunpetch V, et al. The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials. 2021;268: 120555.

    Article  CAS  Google Scholar 

  7. Haseeb A, Haqqi TM. Immunopathogenesis of osteoarthritis. Clin Immunol. 2013;146(3):185–96.

    Article  CAS  Google Scholar 

  8. Ye B, Chen X, Dai S, et al. Emodin alleviates myocardial ischemia/reperfusion injury by inhibiting gasdermin D-mediated pyroptosis in cardiomyocytes. Drug Des Devel Ther. 2019;13:975–90.

    Article  CAS  Google Scholar 

  9. Man SM, Karki R, Kanneganti TD. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 2017;277(1):61–75.

    Article  CAS  Google Scholar 

  10. Zhang Y, Lin Z, Chen D, et al. CY-09 attenuates the progression of osteoarthritis via inhibiting NLRP3 inflammasome-mediated pyroptosis. Biochem Biophys Res Commun. 2021;553:119–25.

    Article  CAS  Google Scholar 

  11. Liu X, Zhang Z, Ruan J, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–8.

    Article  CAS  Google Scholar 

  12. Mcallister MJ, Chemaly M, Eakin AJ, et al. NLRP3 as a potentially novel biomarker for the management of osteoarthritis. Osteoarth Cartil. 2018;26(5):612–9.

    Article  CAS  Google Scholar 

  13. Olee T, Hashimoto S, Quach J, et al. IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses. J Immunol. 1999;162(2):1096–100.

    Article  CAS  Google Scholar 

  14. Bougault C, Gosset M, Houard X, et al. Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models. Arthritis Rheum. 2012;64(12):3972–81.

    Article  CAS  Google Scholar 

  15. Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat Rev Rheumatol. 2012;8(7):390–8.

    Article  CAS  Google Scholar 

  16. Harrell CR, Markovic BS, Fellabaum C, et al. Mesenchymal stem cell-based therapy of osteoarthritis: current knowledge and future perspectives. Biomed Pharmacother. 2019;109:2318–26.

    Article  CAS  Google Scholar 

  17. Zhao X, Zhao Y, Sun X, et al. Immunomodulation of MSCs and MSC-derived extracellular vesicles in osteoarthritis. Front Bioeng Biotechnol. 2020;8: 575057.

    Article  Google Scholar 

  18. Dubey NK, Wei H-J, Yu S-H, et al. Adipose-derived stem cells attenuates diabetic osteoarthritis via inhibition of glycation-mediated inflammatory cascade. Aging Dis. 2019;10(3):483–96.

    Article  Google Scholar 

  19. Xie X, Wang Y, Zhao C, et al. Comparative evaluation of MSCs from bone marrow and adipose tissue seeded in PRP-derived scaffold for cartilage regeneration. Biomaterials. 2012;33(29):7008–18.

    Article  CAS  Google Scholar 

  20. Taléns-Visconti R, Bonora A, Jover R, et al. Hepatogenic differentiation of human mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells. World J Gastroenterol. 2006;12(36):5834–45.

    Article  Google Scholar 

  21. Zhang HT, Liu ZL, Yao XQ, et al. Neural differentiation ability of mesenchymal stromal cells from bone marrow and adipose tissue: a comparative study. Cytotherapy. 2012;14(10):1203–14.

    Article  CAS  Google Scholar 

  22. Gao J, Yuan J, Liu Q, et al. Adipose-derived stem cells therapy effectively attenuates PM(2.5)-induced lung injury. Stem Cell Res Ther. 2021;12(1):355.

  23. Wang J, Ren H, Yuan X, et al. Interleukin-10 secreted by mesenchymal stem cells attenuates acute liver failure through inhibiting pyroptosis. Hepatol Res. 2018;48(3):E194-e202.

    Article  CAS  Google Scholar 

  24. Robert AW, Marcon BH, Dallagiovanna B, et al. Adipogenesis, osteogenesis, and chondrogenesis of human mesenchymal stem/stromal cells: a comparative transcriptome approach. Front Cell Dev Biol. 2020;8:561.

    Article  Google Scholar 

  25. Liu F, Yang H, Li D, et al. Punicalagin attenuates osteoarthritis progression via regulating Foxo1/Prg4/HIF3α axis. Bone. 2021;152: 116070.

    Article  CAS  Google Scholar 

  26. Gerwin N, Bendele AM, Glasson S, et al. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the rat. Osteoarthritis Cartilage. 2010;18(Suppl 3):S24-34.

    Article  Google Scholar 

  27. Wu X, Ren G, Zhou R, et al. The role of Ca(2+) in acid-sensing ion channel 1a-mediated chondrocyte pyroptosis in rat adjuvant arthritis. Lab Invest. 2019;99(4):499–513.

    Article  CAS  Google Scholar 

  28. Shi J, Liang J, Guo B, et al. Adipose-derived stem cells cocultured with chondrocytes promote the proliferation of chondrocytes. Stem Cells Int. 2017;2017:1709582.

    Article  Google Scholar 

  29. Xia B, Di C, Zhang J, et al. Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int. 2014;95(6):495–505.

    Article  CAS  Google Scholar 

  30. Glyn-Jones S, Palmer AJ, Agricola R, et al. Osteoarthritis. Lancet. 2015;386(9991):376–87.

    Article  CAS  Google Scholar 

  31. Li Z, Huang Z, Zhang H, et al. P2X7 receptor induces pyroptotic inflammation and cartilage degradation in osteoarthritis via NF-κB/NLRP3 crosstalk. Oxid Med Cell Longev. 2021;2021:8868361.

    Google Scholar 

  32. Chow YY, Chin KY. The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm. 2020;2020:8293921.

    Article  Google Scholar 

  33. Wang C, Gao Y, Zhang Z, et al. Safflower yellow alleviates osteoarthritis and prevents inflammation by inhibiting PGE2 release and regulating NF-κB/SIRT1/AMPK signaling pathways. Phytomedicine. 2020;78: 153305.

    Article  CAS  Google Scholar 

  34. Zhang L, Zhang L, Huang Z, et al. Increased HIF-1α in knee osteoarthritis aggravate synovial fibrosis via fibroblast-like synoviocyte pyroptosis. Oxid Med Cell Longev. 2019;2019:6326517.

    Google Scholar 

  35. Zhang L, Xing R, Huang Z, et al. Inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in knee osteoarthritis. Mediators Inflamm. 2019;2019:2165918.

    Article  Google Scholar 

  36. Sharma D, Malik A, Guy C, et al. TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy. J Clin Invest. 2019;129(1):150–62.

    Article  Google Scholar 

  37. Mcgeough MD, Wree A, Inzaugarat ME, et al. TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies. J Clin Invest. 2017;127(12):4488–97.

    Article  Google Scholar 

  38. An S, Hu H, Li Y, et al. Pyroptosis plays a role in osteoarthritis. Aging Dis. 2020;11(5):1146–57.

    Article  Google Scholar 

  39. Clavijo-Cornejo D, Martínez-Flores K, Silva-Luna K, et al. The overexpression of NALP3 inflammasome in knee osteoarthritis is associated with synovial membrane prolidase and NADPH oxidase 2. Oxid Med Cell Longev. 2016;2016:1472567.

    Article  Google Scholar 

  40. Tseng WY, Huang YS, Lin HH, et al. TNFR signalling and its clinical implications. Cytokine. 2018;101:19–25.

    Article  CAS  Google Scholar 

  41. De Bari C, Roelofs AJ. Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. Curr Opin Pharmacol. 2018;40:74–80.

    Article  Google Scholar 

  42. Childs PG, Reid S, Salmeron-Sanchez M, et al. Hurdles to uptake of mesenchymal stem cells and their progenitors in therapeutic products. Biochem J. 2020;477(17):3349–66.

    Article  CAS  Google Scholar 

  43. Lee WS, Kim HJ, Kim KI, et al. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. Stem Cells Transl Med. 2019;8(6):504–11.

    Article  CAS  Google Scholar 

  44. Freitag J, Bates D, Wickham J, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med. 2019;14(3):213–30.

    Article  CAS  Google Scholar 

  45. Wang W, Cao W. Treatment of osteoarthritis with mesenchymal stem cells. Sci China Life Sci. 2014;57(6):586–95.

    Article  CAS  Google Scholar 

  46. Mianehsaz E, Mirzaei HR, Mahjoubin-Tehran M, et al. Mesenchymal stem cell-derived exosomes: a new therapeutic approach to osteoarthritis? Stem Cell Res Ther. 2019;10(1):340.

    Article  Google Scholar 

  47. Liang H, Ding X, Yu Y, et al. Adipose-derived mesenchymal stem cells ameliorate acute liver injury in rat model of CLP induced-sepsis via sTNFR1. Exp Cell Res. 2019;383(1): 111465.

    Article  CAS  Google Scholar 

  48. Ke F, Zhang L, Liu Z, et al. Soluble tumor necrosis factor receptor 1 released by skin-derived mesenchymal stem cells is critical for inhibiting Th17 cell differentiation. Stem Cells Transl Med. 2016;5(3):301–13.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are very grateful to Fanjiang Meng, who was employed by Bopin Biopharma Co., Ltd, for providing us with human adipose-derived mesenchymal stem cells. And we are particularly grateful to the support of the Center for Scientific Research of Anhui Medical University.

Author information

Authors and Affiliations

  1. Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China

    Liang Xu, Feng Zhang, Gang Cheng, Xiaoyang Yuan, Yujiao Wu, Huaxun Wu, Qingtong Wang, Jingyu Chen, Jiajie Kuai, Yan Chang, Wei Wei & Shangxue Yan

  2. Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Hefei, China

    Liang Xu, Feng Zhang, Gang Cheng, Xiaoyang Yuan, Yujiao Wu, Huaxun Wu, Qingtong Wang, Jingyu Chen, Jiajie Kuai, Yan Chang, Wei Wei & Shangxue Yan

  3. Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, China

    Liang Xu, Feng Zhang, Gang Cheng, Xiaoyang Yuan, Yujiao Wu, Huaxun Wu, Qingtong Wang, Jingyu Chen, Jiajie Kuai, Yan Chang, Wei Wei & Shangxue Yan

Authors
  1. Liang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaoyang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yujiao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huaxun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qingtong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jingyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jiajie Kuai
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yan Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shangxue Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LX: conceptualization, methodology, software, validation, writing—original draft. FZ: investigation, resources. Gang cheng: investigation, resources. XY: investigation, resources. YW: investigation, resources. HW: writing—review and editing, formal analysis. QW: validation, formal analysis. JC: data curation, visualization. JK: data curation, visualization. YC: data curation, visualization. WW: writing—review and editing, project administration, supervision. SY: conceptualization, methodology, writing—review and editing, project administration, funding acquisition, supervision. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Wei Wei or Shangxue Yan.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, L., Zhang, F., Cheng, G. et al. Attenuation of experimental osteoarthritis with human adipose-derived mesenchymal stem cell therapy: inhibition of the pyroptosis in chondrocytes. Inflamm. Res. 72, 89–105 (2023). https://doi.org/10.1007/s00011-022-01655-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-022-01655-2

Keywords

Search

Navigation