Skip to main content

Advertisement

SpringerLink
Log in

Anti-inflammatory capacity of Apremilast in human chondrocytes is dependent on SOX-9

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

Abstract

Background and purpose

Osteoarthritis (OA) impacts the quality of life in middle-aged and elderly people by inducing immobility. The severe inflammation in chondrocytes is reported to be related to the development and process of OA. The present study aims to investigate the protective effects of Apremilast on injured chondrocytes induced by interleukin-1α (IL-1α) and the underlying mechanism.

Methods

10 ng/mL IL-1α was used to induce the in vitro injured chondrocytes. QRT-PCR was used to evaluate the expression level of Sry-type high-mobility-group box 9 (SOX-9), collagen type II alpha-1 gene (COL2A1), Aggrecan (ACAN) and collagen type X alpha 1 chain (COL10A1). SiRNA technology was utilized to knock down the expression of SOX-9 in the chondrocytes. The expression of SOX-9 was determined by Western Blot assay and/or immunofluorescence assay. Western Blot was used to evaluate the expression level of phosphorylated cyclic AMP response element binding (CREB).

Results

SOX9, Col2a1 and Acan were significantly up-regulated and Col10a1 was significantly down-regulated in the chondrocytes by Apremilast in a dose-dependent manner. IL-1α induced the injured chondrocytes by decreasing the expression of SOX9, Col2a1, Acan and increasing the expression of Col10a1, which were greatly reversed by Apremilast. By silencing SOX-9, the effects of Apremilast on SOX9 and marker genes were abolished. Phosphorylated CREB was up-regulated by Apremilast in a time-dependent manner. The up-regulated SOX-9 by Apremilast was reversed by the protein kinase A (PKA)/CREB pathway inhibitor H89.

Conclusion

Apremilast may protect chondrocytes from inflammation by up-regulating SOX9.

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. Pelletier JP, et al. Immunological analysis of proteoglycan structural changes in the early stage of experimental osteoarthritic canine cartilage lesions. J Orthop Res. 1992;10(4):511–23.

    Article  CAS  Google Scholar 

  2. Adams ME. Cartilage hypertrophy following canine anterior cruciate ligament transection differs among different areas of the joint. J Rheumatol. 1989;16(6):818–24.

    CAS  PubMed  Google Scholar 

  3. Abramson SB, Attur M. Developments in the scientific understanding of osteoarthritis. Arthritis Res Ther. 2009;11(3):227.

    Article  Google Scholar 

  4. Fitzgerald GK, Piva SR, Irrgang JJ. Reports of joint instability in knee osteoarthritis: its prevalence and relationship to physical function. Arthritis Rheum. 2004;51(6):941–6.

    Article  Google Scholar 

  5. Hayashi D, Roemer FW, Guermazi A. Imaging for osteoarthritis. Ann Phys Rehabil Med. 2016;59(3):161–9.

    Article  CAS  Google Scholar 

  6. Carames B, et al. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 2010;62(3):791–801.

    Article  CAS  Google Scholar 

  7. Kim HA, Blanco FJ. Cell death and apoptosis in osteoarthritic cartilage. Curr Drug Targets. 2007;8(2):333–45.

    Article  CAS  Google Scholar 

  8. Taniguchi N, et al. Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis. Proc Natl Acad Sci U S A. 2009;106(4):1181–6.

    Article  CAS  Google Scholar 

  9. Johnson EO, et al. Apoptosis in osteoarthritis: morphology, mechanisms, and potential means for therapeutic intervention. J Surg Orthop Adv. 2008;17(3):147–52.

    PubMed  Google Scholar 

  10. Marks PH, Donaldson ML. Inflammatory cytokine profiles associated with chondral damage in the anterior cruciate ligament-deficient knee. Arthroscopy. 2005;21(11):1342–7.

    Article  Google Scholar 

  11. Verdonk P, et al. Cyclodextrin polysulphates repress IL-1 and promote the accumulation of chondrocyte extracellular matrix. Osteoarthr Cart. 2005;13(10):887–95.

    Article  CAS  Google Scholar 

  12. Bar Oz M, et al. Acetylation reduces SOX9 nuclear entry and ACAN gene transactivation in human chondrocytes. Aging Cell. 2016;15(3):499–508.

    Article  CAS  Google Scholar 

  13. Otero M, et al. ELF3 modulates type II collagen gene (COL2A1) transcription in chondrocytes by inhibiting SOX9-CBP/p300-driven histone acetyltransferase activity. Connect Tissue Res. 2017;58(1):15–26.

    Article  CAS  Google Scholar 

  14. Li C, et al. MicroRNA-140 suppresses human chondrocytes hypertrophy by targeting SMAD1 and controlling the bone morphogenetic protein pathway in osteoarthritis. Am J Med Sci. 2018;355(5):477–87.

    Article  Google Scholar 

  15. Keating GM. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs. 2017;77(4):459–72.

    Article  CAS  Google Scholar 

  16. Bi W, et al. Sox9 is required for cartilage formation. Nat Genet. 1999;22(1):85–9.

    Article  CAS  Google Scholar 

  17. Stokes DG, et al. Regulation of type-II collagen gene expression during human chondrocyte de-differentiation and recovery of chondrocyte-specific phenotype in culture involves Sry-type high-mobility-group box (SOX) transcription factors. Biochem J. 2001;360(Pt 2):461–70.

    Article  CAS  Google Scholar 

  18. Cao L, et al. The promotion of cartilage defect repair using adenovirus mediated Sox9 gene transfer of rabbit bone marrow mesenchymal stem cells. Biomaterials. 2011;32(16):3910–20.

    Article  CAS  Google Scholar 

  19. Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011;23(5):471–8.

    Article  CAS  Google Scholar 

  20. Kolettas E, et al. Chondrocyte phenotype and cell survival are regulated by culture conditions and by specific cytokines through the expression of SOX-9 transcription factor. Rheumatol (Oxf). 2001;40(10):1146–56.

    Article  CAS  Google Scholar 

  21. Perera PM, et al. Mechanical signals control SOX-9, VEGF, and c-Myc expression and cell proliferation during inflammation via integrin-linked kinase, B-Raf, and ERK1/2-dependent signaling in articular chondrocytes. Arthritis Res Ther. 2010;12(3):R106.

    Article  Google Scholar 

  22. Lee HJ, et al. Membrane-free stem cell components inhibit interleukin-1alpha-stimulated inflammation and cartilage degradation in vitro and in vivo: a rat model of osteoarthritis. Int J Mol Sci. 2019;20(19):4869.

    Article  CAS  Google Scholar 

  23. Deffaud J, et al. Modulatory effect of rhein on IL-1alpha-induced responses in human chondrocytes: a comparative study between antibody microarrays and specific ELISAs. Biorheology. 2008;45(3–4):439–55.

    Article  CAS  Google Scholar 

  24. Ikegami D, et al. Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development. 2011;138(8):1507–19.

    Article  CAS  Google Scholar 

  25. Akiyama H, et al. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002;16(21):2813–28.

    Article  CAS  Google Scholar 

  26. Aigner T, Stove J. Collagens–major component of the physiological cartilage matrix, major target of cartilage degeneration, major tool in cartilage repair. Adv Drug Deliv Rev. 2003;55(12):1569–93.

    Article  CAS  Google Scholar 

  27. van den Berg WB. Osteoarthritis year 2010 in review: pathomechanisms. Osteoarthr Cart. 2011;19(4):338–41.

    Article  Google Scholar 

  28. Hu G, Codina M, Fisher S. Multiple enhancers associated with ACAN suggest highly redundant transcriptional regulation in cartilage. Matrix Biol. 2012;31(6):328–37.

    Article  CAS  Google Scholar 

  29. Diederichs S, et al. Chondral differentiation of induced pluripotent stem cells without progression into the endochondral pathway. Front Cell Dev Biol. 2019;7:270.

    Article  Google Scholar 

  30. Huang H, et al. Dose-specific effects of tumor necrosis factor alpha on osteogenic differentiation of mesenchymal stem cells. Cell Prolif. 2011;44(5):420–7.

    Article  CAS  Google Scholar 

  31. Siddappa R, et al. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. Proc Natl Acad Sci USA. 2008;105(20):7281–6.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedics, Luoyang Orthopedic Hospital of Henan Province (Orthopedic Hospital of Henan Province), No. 82 South Qi Ming Road, Luoyang, 471002, Henan, China

    Yanjie Zhang, Xiaohan Huang & Yanhao Yuan

Authors
  1. Yanjie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaohan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanhao Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yanjie Zhang.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Huang, X. & Yuan, Y. Anti-inflammatory capacity of Apremilast in human chondrocytes is dependent on SOX-9. Inflamm. Res. 69, 1123–1132 (2020). https://doi.org/10.1007/s00011-020-01392-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-020-01392-4

Keywords

Search

Navigation