Skip to main content
Springer Nature Link
Log in

1,25(OH)2D3 induces chondrocyte autophagy and reduces the loss of proteoglycans in osteoarthritis through inhibiting the NF-κB pathway

  • ORIGINAL ARTICLE
  • Published:
Clinical Rheumatology Aims and scope Submit manuscript

Abstract

Objective

Nuclear transcription factor-κB (NF-κB) activation is a pivotal event in the pathogenesis of osteoarthritis (OA). OA patients frequently exhibit vitamin D (VD) deficiency, which is commonly associated with NF-κB activation. Our study aimed to investigate whether VD could protect against OA by modulating NF-κB pathway and to explore the underlying mechanisms.

Methods

Proteins levels were assessed by western blot analysis, gene expression was quantified by quantitative real-time polymerase chain reaction (qRT‒PCR) in vivo and in vitro. The expression of phosphorylated-p65 (p-p65) in knee OA rats was detected by immunohistochemistry, and an NF-κB nuclear translocation assay was validated in chondrocytes. Immunoprecipitation was employed to detect the interaction between NF-κB and vitamin D receptor (VDR) in vivo and in vitro. Small interfering RNA (Si-NF-κB and Si-VDR) transfection was used to investigate the role of NF-κB and VDR signaling pathway in knee OA rats under VD influence. Cartilage changes were visualized of knee OA rats using hematoxylin and eosin as well as safranin-O/fast green of staining.

Results

Our findings indicated that VD alleviates OA by inhibiting NF-κB pathway, which in turn reduces chondrocyte apoptosis and extracellular matrix (ECM) degradation. Further analysis revealed that VD primarily stabilizes NF-κB through the interaction of VDR and NF-κB, modulating the AMPK/mTOR signaling pathway to enhance autophagy and delay the progression of OA.

Conclusion

This study highlights the protective role of VD in OA by stabilization of NF-κB, mainly through the interaction between VDR and NF-κB. This interaction regulates the AMPK/mTOR signaling pathway, promoting autophagy and suggesting a potential therapeutic strategy for OA management.

Key Points

• VD confers a protective effect on OA by primarily stabilizing NF-κB through the interaction between VDR and NF-κB, which in turn inhibits NF-κB phosphorylation and nuclear translocation.

• In chondrocytes, VD helps shield against OA by blocking NF-κB’s entry into the nucleus, subsequently regulating autophagy via the AMPK/mTOR signaling pathway.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Data Availability

The datasets presented in this study are available from the corresponding authors with reasonable requests.

References

  1. Hunter DJB-ZS (2019) Osteoarthritis. Lancet 393(10182):1745–1759. https://doi.org/10.1016/S0140-6736(19)30417-9

    Article  PubMed  Google Scholar 

  2. Adam MS, Zhuang H, Ren X, Zhang Y, Zhou P (2024) The metabolic characteristics and changes of chondrocytes in vivo and in vitro in osteoarthritis. Front Endocrinol 15:1393550. https://doi.org/10.3389/fendo.2024.1393550

    Article  Google Scholar 

  3. Pettenuzzo S, Arduino A, Belluzzi E, Pozzuoli A, Fontanella CG, Ruggieri P, Salomoni V, Majorana C, Berardo A (2023) Biomechanics of chondrocytes and chondrons in healthy conditions and osteoarthritis: a review of the mechanical characterisations at the microscale. Biomedicines 11(7):1942. https://doi.org/10.3390/biomedicines11071942

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jang S, Lee K, Ju JH (2021) Recent updates of diagnosis, pathophysiology, and treatment on osteoarthritis of the knee. Int J Mol Sci 22(5):2619. https://doi.org/10.3390/ijms22052619

    Article  PubMed  PubMed Central  Google Scholar 

  5. Deng Y, Lu J, Li W, Wu A, Zhang X, Tong W, Ho KK, Qin L, Song H, Mak KK (2018) Reciprocal inhibition of YAP/TAZ and NF-kappaB regulates osteoarthritic cartilage degradation. Nat Commun 9(1):4564. https://doi.org/10.1038/s41467-018-07022-2

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yu H, Lin L, Zhang Z, Zhang H, Hu H (2020) Targeting NF-kappaB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther 5(1):209. https://doi.org/10.1038/s41392-020-00312-6

    Article  PubMed  PubMed Central  Google Scholar 

  7. Roman-Blas JA, Jimenez SA (2006) NF-kappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage 14(9):839–848. https://doi.org/10.1016/j.joca.2006.04.008

    Article  PubMed  Google Scholar 

  8. Choi MC, Jo J, Park J, Kang HK, Park Y (2019) NF-kappaB signaling pathways in osteoarthritic cartilage destruction. Cells 8(7):734. https://doi.org/10.3390/cells8070734

    Article  PubMed  PubMed Central  Google Scholar 

  9. Campbell KA, Minashima T, Zhang Y, Hadley S, Lee YJ, Giovinazzo J, Quirno M, Kirsch T (2013) Annexin A6 interacts with p65 and stimulates NF-kappaB activity and catabolic events in articular chondrocytes. Arthritis Rheum 65(12):3120–3129. https://doi.org/10.1002/art.38182

    Article  PubMed  Google Scholar 

  10. Tang S, Nie X, Ruan J, Cao Y, Kang J, Ding C (2022) Circular RNA circNFKB1 promotes osteoarthritis progression through interacting with ENO1 and sustaining NF-kappaB signaling. Cell Death Dis 13(8):695. https://doi.org/10.1038/s41419-022-05148-2

    Article  PubMed  PubMed Central  Google Scholar 

  11. Christakos S, Li S, De La Cruz J, Bikle DD (2019) New developments in our understanding of vitamin metabolism, action and treatment. Metabolism 98:112–120. https://doi.org/10.1016/j.metabol.2019.06.010

    Article  PubMed  PubMed Central  Google Scholar 

  12. Charoenngam N, Holick MF (2020) Immunologic effects of vitamin D on human health and disease. Nutrients 12(7):2097. https://doi.org/10.3390/nu12072097

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wu S, Xia Y, Liu X, Sun J (2010) Vitamin D receptor deletion leads to reduced level of IkappaBalpha protein through protein translation, protein-protein interaction, and post-translational modification. Int J Biochem Cell Biol 42(2):329–336. https://doi.org/10.1016/j.biocel.2009.11.012

    Article  PubMed  Google Scholar 

  14. Sun J, Kong J, Duan Y, Szeto FL, Liao A, Madara JL, Li YC (2006) Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor. Am J Physiol Endocrinol Metab 291(2):E315–E322. https://doi.org/10.1152/ajpendo.00590.2005

    Article  PubMed  Google Scholar 

  15. Tan X, Wen X, Liu Y (2008) Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-kappaB signaling. J Am Soc Nephrol 19(9):1741–1752. https://doi.org/10.1681/ASN.2007060666

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chen YH, Yu Z, Fu L, Wang H, Chen X, Zhang C, Lv ZM, Xu DX (2015) Vitamin D3 inhibits lipopolysaccharide-induced placental inflammation through reinforcing interaction between vitamin D receptor and nuclear factor kappa B p65 subunit. Sci Rep 5:10871. https://doi.org/10.1038/srep10871

    Article  PubMed  PubMed Central  Google Scholar 

  17. Xu S, Chen Y-H, Tan Z-X, Xie D-D, Zhang C, Zhang Z-H, Wang H, Zhao H, Yu D-X, Xu D-X (2015) Vitamin D3 pretreatment regulates renal inflammatory responses during lipopolysaccharide-induced acute kidney injury. Sci Rep 5(1):18687. https://doi.org/10.1038/srep18687

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ma D, Zhang RN, Wen Y, Yin WN, Bai D, Zheng GY, Li JS, Zheng B, Wen JK (2017) 1, 25(OH)(2)D(3)-induced interaction of vitamin D receptor with p50 subunit of NF-kappaB suppresses the interaction between KLF5 and p50, contributing to inhibition of LPS-induced macrophage proliferation. Biochem Biophys Res Commun 482(2):366–374. https://doi.org/10.1016/j.bbrc.2016.11.069

    Article  PubMed  Google Scholar 

  19. Glasson SS, Blanchet TJ, Morris EA (2007) The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15(9):1061–1069. https://doi.org/10.1016/j.joca.2007.03.006

    Article  PubMed  Google Scholar 

  20. Zhang Z, Huang C, Jiang Q, Zheng Y, Liu Y, Liu S, Chen Y, Mei Y, Ding C, Chen M, Gu X, Xing D, Gao M, He L, Ye Z, Wu L, Xu J, Yang P, Zhang X, Zhang Y, Chen J, Lin J, Zhao L, Li M, Yang W, Zhou Y, Jiang Q, Chu C-Q, Chen Y, Zhang W, Tsai W-C, Lei G, He D, Liu W, Fang Y, Wu D, Lin J, Wei C-C, Lin H-Y, Zeng X (2020) Guidelines for the diagnosis and treatment of osteoarthritis in China (2019 edition). Ann Transl Med 8(19):1213. https://doi.org/10.21037/atm-20-4665

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kelgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Ann Rheum Dis 16(4):494–502. https://doi.org/10.1136/ard.16.4.494

    Article  Google Scholar 

  22. Glasson SS, Chambers MG, Van Den Berg WB, Little CB (2010) The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 18(Suppl 3):S17–S23. https://doi.org/10.1016/j.joca.2010.05.025

    Article  PubMed  Google Scholar 

  23. Zhang XH, Zheng B, Gu C, Fu JR, Wen JK (2012) TGF-beta1 downregulates AT1 receptor expression via PKC-delta-mediated Sp1 dissociation from KLF4 and Smad-mediated PPAR-gamma association with KLF4. Arterioscler Thromb Vasc Biol 32(4):1015–1023. https://doi.org/10.1161/ATVBAHA.111.244962

    Article  PubMed  Google Scholar 

  24. Liu PZJ, Cui H, Xu J, Ruan G, Ding C, Wang K (2024) Vitamin D plays a protective role in osteoarthritis by regulating AMPK/mTOR signalling pathway to activate chondrocyte autophagy. Clin Exp Rheumatol 42(3):736–745. https://doi.org/10.55563/clinexprheumatol/chmuts

    Article  PubMed  Google Scholar 

  25. Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, Carr AJ (2015) Osteoarthritis Lancet 386(9991):376–387. https://doi.org/10.1016/S0140-6736(14)60802-3

    Article  PubMed  Google Scholar 

  26. Yan H, Duan X, Pan H, Holguin N, Rai MF, Akk A, Springer LE, Wickline SA, Sandell LJ, Pham CT (2016) Suppression of NF-kappaB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury. Proc Natl Acad Sci U S A 113(41):E6199–E6208. https://doi.org/10.1073/pnas.1608245113

    Article  PubMed  PubMed Central  Google Scholar 

  27. Duan LMY, Wang Y, Liu J, Tan Z, Wu Q, Wu Y, Yu X (2020) Infrapatellar fat pads participate in the development of knee osteoarthritis in obese patients via the activation of the NF-κB signaling pathway. Int J Mol Med 46(6):2260–2270. https://doi.org/10.3892/ijmm.2020.4739

    Article  PubMed  Google Scholar 

  28. Li Y, Jiang W, Wang H, Deng Z, Zeng C, Tu M, Li L, Xiao W, Gao S, Luo W, Lei G (2016) Osteopontin promotes expression of matrix metalloproteinase 13 through NF-kappaB signaling in osteoarthritis. Biomed Res Int 2016:6345656. https://doi.org/10.1155/2016/6345656

    Article  PubMed  PubMed Central  Google Scholar 

  29. Ding Y, Wang L, Zhao Q, Wu Z, Kong L (2019) MicroRNA-93 inhibits chondrocyte apoptosis and inflammation in osteoarthritis by targeting the TLR4/NF-kappaB signaling pathway. Int J Mol Med 43(2):779–790. https://doi.org/10.3892/ijmm.2018.4033

    Article  PubMed  Google Scholar 

  30. Tianyang Gao WG (2016) Mingxue Chen, Jingxiang Huang, Zhiguo Yuan (2016) Extracellular vesicles and autophagy in osteoarthritis. BioMed Res Int 8:1–8. https://doi.org/10.1155/2016/2428915

    Article  Google Scholar 

  31. Mabey T, Honsawek S (2015) Role of vitamin D in osteoarthritis: molecular, cellular, and clinical perspectives. Int J Endocrinol. 2015:383918. https://doi.org/10.1155/2015/383918

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sun J (2016) VDR/vitamin D receptor regulates autophagic activity through ATG16L1. Autophagy 12(6):1057–1058. https://doi.org/10.1080/15548627.2015.1072670

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We sincerely acknowledge the Centre for Scientific Research of Anhui Medical University and Centre for Scientific Research of the First Affiliated Hospital of Anhui Medical University foe valuable help in our experiments.

Funding

This research was funded by the National Natural Science Foundation of China (Grant No. 81802201).

Author information

Authors and Affiliations

  1. Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, China

    Pingping Liu, Junxian Zhou, Jianhua Xu & Kang Wang

  2. Department of Rheumatology and Immunology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, China

    Pingping Liu

  3. Zhaoke Pharmaceutical Hefei Co, Hefei, 230000, China

    Haigang Cui

  4. Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, China

    Guangfeng Ruan & Changhai Ding

Authors
  1. Pingping Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Junxian Zhou
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Haigang Cui
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Jianhua Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Guangfeng Ruan
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Changhai Ding
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Kang Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Kang Wang.

Ethics declarations

Disclosures

None.

Statement of ethics and consent

All procedures were approved by the Experimental Animal Ethics Committee of Anhui Medical University (Approval No: LLSC20211506). Consent for sample procurement was obtained from the donors, adhering strictly to the ethical guidelines of China and the principle of the Helsinki Declaration.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 163 KB)

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

Liu, P., Zhou, J., Cui, H. et al. 1,25(OH)2D3 induces chondrocyte autophagy and reduces the loss of proteoglycans in osteoarthritis through inhibiting the NF-κB pathway. Clin Rheumatol 44, 811–822 (2025). https://doi.org/10.1007/s10067-024-07281-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10067-024-07281-z

Keywords