Skip to main content

Advertisement

SpringerLink
Log in

MicroRNA-142-3p Inhibits Chondrocyte Apoptosis and Inflammation in Osteoarthritis by Targeting HMGB1

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation and joint inflammation in which microRNAs are significantly involved. Previous studies have reported that miR-142-3p is a novel mediator of inflammatory signaling pathways, but whether miR-142-3p regulates OA remains unknown. In this study, we aimed to investigate the potential role of miR-142-3p in OA and the underlying molecular mechanism. We showed that miR-142-3p was significantly reduced in the articular cartilage tissues from experimental OA mice. The expression of miR-142-3p was also decreased in chondrocytes treated with lipopolysaccharide (LPS) in vitro. Moreover, the overexpression of miR-142-3p significantly inhibited cell apoptosis, nuclear factor (NF)-kB, and the production of proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α induced by LPS. Interestingly, bioinformatics analysis demonstrated that high mobility group box 1 (HMGB1), an important inflammatory mediator of OA, was predicted as a target of miR-142-3p, which was validated by dual-luciferase reporter assay. The high expression of HMGB1 in chondrocytes induced by LPS was significantly inhibited by miR-142-3p overexpression. Furthermore, the restoration of HMGB1 markedly abrogated the effect of miR-142-3p. In OA mice, the overexpression of miR-142-3p by lentivirus-mediated gene transfer significantly inhibited HMGB1 expression, NF-kB signaling, and proinflammatory cytokines. Moreover, the overexpression of miR-142-3p significantly alleviated OA progression in OA mice in vivo. Taken together, our study suggests that miR-142-3p inhibits chondrocyte apoptosis and inflammation in OA by inhibiting the HMGB1-mediated NF-kB signaling pathway. The overexpression of miR-142-3p impedes the OA progression in mice in vivo indicating that miR-142-3p is a potential molecular target for OA treatment.

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.

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

Similar content being viewed by others

Abbreviations

OA:

osteoarthritis

miRNAs:

microRNAs

LPS:

lipopolysaccharide

IL:

interleukin

TNF-α:

tumor necrosis factor α

NF-kB:

nuclear factor-kB

HMGB1:

high mobility group box 1

References

  1. Taruc-Uy, R.L., and S.A. Lynch. 2013. Diagnosis and treatment of osteoarthritis. Primary Care 40: 821–836. vii.

    Article  PubMed  Google Scholar 

  2. Swingler, T.E., G. Wheeler, V. Carmont, H.R. Elliott, M.J. Barter, M. Abu-Elmagd, S.T. Donell, R.P. Boot-Handford, M.K. Hajihosseini, A. Munsterberg, et al. 2012. The expression and function of microRNAs in chondrogenesis and osteoarthritis. Arthritis and Rheumatism 64: 1909–1919.

    Article  CAS  PubMed  Google Scholar 

  3. Goldring, M.B. 2012. Chondrogenesis, chondrocyte differentiation, and articular cartilage metabolism in health and osteoarthritis. Therapeutic Advances in Musculoskeletal Disorders 4: 269–285.

    Article  CAS  Google Scholar 

  4. Blanco, F.J., R. Guitian, E. Vazquez-Martul, F.J. de Toro, and F. Galdo. 1998. Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis and Rheumatism 41: 284–289.

    Article  CAS  PubMed  Google Scholar 

  5. Qin, J., L. Shang, A.S. Ping, J. Li, X.J. Li, H. Yu, J. Magdalou, L.B. Chen, and H. Wang. 2012. TNF/TNFR signal transduction pathway-mediated anti-apoptosis and anti-inflammatory effects of sodium ferulate on IL-1beta-induced rat osteoarthritis chondrocytes in vitro. Arthritis Research and Therapy 14: R242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vicente, R., D. Noel, Y.M. Pers, F. Apparailly, and C. Jorgensen. 2015. Deregulation and therapeutic potential of microRNAs in arthritic diseases. Nature Reviews. Rheumatology 12(4): 211–220.

    Article  PubMed  Google Scholar 

  7. Mendell, J.T., and E.N. Olson. 2012. MicroRNAs in stress signaling and human disease. Cell 148: 1172–1187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bartel, D.P. 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281–297.

    Article  CAS  PubMed  Google Scholar 

  9. Winter, J., S. Jung, S. Keller, R.I. Gregory, and S. Diederichs. 2009. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nature Cell Biology 11: 228–234.

    Article  CAS  PubMed  Google Scholar 

  10. Croce, C.M., and G.A. Calin. 2005. miRNAs, cancer, and stem cell division. Cell 122: 6–7.

    Article  CAS  PubMed  Google Scholar 

  11. Lu, B., C. Wang, M. Wang, W. Li, F. Chen, K.J. Tracey, and H. Wang. 2014. Molecular mechanism and therapeutic modulation of high mobility group box 1 release and action: an updated review. Expert Review of Clinical Immunology 10: 713–727.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tian, J., A.M. Avalos, S.Y. Mao, B. Chen, K. Senthil, H. Wu, P. Parroche, S. Drabic, D. Golenbock, C. Sirois, et al. 2007. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunology 8: 487–496.

    Article  CAS  PubMed  Google Scholar 

  13. Yu, M., H. Wang, A. Ding, D.T. Golenbock, E. Latz, C.J. Czura, M.J. Fenton, K.J. Tracey, and H. Yang. 2006. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock 26: 174–179.

    Article  CAS  PubMed  Google Scholar 

  14. Fiuza, C., M. Bustin, S. Talwar, M. Tropea, E. Gerstenberger, J.H. Shelhamer, and A.F. Suffredini. 2003. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood 101: 2652–2660.

    Article  CAS  PubMed  Google Scholar 

  15. Ley, C., S. Ekman, B. Roneus, and M.L. Eloranta. 2009. Interleukin-6 and high mobility group box protein-1 in synovial membranes and osteochondral fragments in equine osteoarthritis. Research in Veterinary Science 86: 490–497.

    Article  CAS  PubMed  Google Scholar 

  16. Heinola, T., V.P. Kouri, P. Clarijs, H. Ciferska, A. Sukura, J. Salo, and Y.T. Konttinen. 2010. High mobility group box-1 (HMGB-1) in osteoarthritic cartilage. Clinical and Experimental Rheumatology 28: 511–518.

    CAS  PubMed  Google Scholar 

  17. Garcia-Arnandis, I., M.I. Guillen, F. Gomar, J.P. Pelletier, J. Martel-Pelletier, and M.J. Alcaraz. 2010. High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1beta in osteoarthritic synoviocytes. Arthritis Research and Therapy 12: R165.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Li, Z.C., G.Q. Cheng, K.Z. Hu, M.Q. Li, W.P. Zang, Y.Q. Dong, W.L. Wang, and Z.D. Liu. 2011. Correlation of synovial fluid HMGB-1 levels with radiographic severity of knee osteoarthritis. Clinical and Investigative Medicine 34: E298.

    CAS  PubMed  Google Scholar 

  19. Yuan, Z., G. Luo, X. Li, J. Chen, J. Wu, and Y. Peng. 2016. PPARgamma inhibits HMGB1 expression through upregulation of miR-142-3p in vitro and in vivo. Cellular Signalling 28: 158–164.

    Article  CAS  PubMed  Google Scholar 

  20. Xu, G., Z. Zhang, J. Wei, Y. Zhang, L. Guo, and X. Liu. 2013. microR-142-3p down-regulates IRAK-1 in response to Mycobacterium bovis BCG infection in macrophages. Tuberculosis (Edinburgh, Scotland) 93: 606–611.

    Article  CAS  Google Scholar 

  21. Gosset, M., F. Berenbaum, S. Thirion, and C. Jacques. 2008. Primary culture and phenotyping of murine chondrocytes. Nature Protocols 3: 1253–1260.

    Article  CAS  PubMed  Google Scholar 

  22. Glasson, S.S., T.J. Blanchet, and E.A. Morris. 2007. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis and Cartilage 15: 1061–1069.

    Article  CAS  PubMed  Google Scholar 

  23. Pritzker, K.P., S. Gay, S.A. Jimenez, K. Ostergaard, J.P. Pelletier, P.A. Revell, D. Salter, and W.B. van den Berg. 2006. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis and Cartilage 14: 13–29.

    Article  CAS  PubMed  Google Scholar 

  24. Luan, Z.G., H. Zhang, P.T. Yang, X.C. Ma, C. Zhang, and R.X. Guo. 2010. HMGB1 activates nuclear factor-kappaB signaling by RAGE and increases the production of TNF-alpha in human umbilical vein endothelial cells. Immunobiology 215: 956–962.

    Article  CAS  PubMed  Google Scholar 

  25. Perri, R., S. Nares, S. Zhang, S.P. Barros, and S. Offenbacher. 2012. MicroRNA modulation in obesity and periodontitis. Journal of Dental Research 91: 33–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pivarcsi, A., F. Meisgen, N. Xu, M. Stahle, and E. Sonkoly. 2013. Changes in the level of serum microRNAs in patients with psoriasis after antitumour necrosis factor-alpha therapy. British Journal of Dermatology 169: 563–570.

    Article  CAS  PubMed  Google Scholar 

  27. Ralfkiaer, U., L.M. Lindahl, T. Litman, L.M. Gjerdrum, C.B. Ahler, R. Gniadecki, T. Marstrand, S. Fredholm, L. Iversen, M.A. Wasik, et al. 2014. MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma. Anticancer Research 34: 7207–7217.

    CAS  PubMed  Google Scholar 

  28. Schaefer, J.S., T. Attumi, A.R. Opekun, B. Abraham, J. Hou, H. Shelby, D.Y. Graham, C. Streckfus, and J.R. Klein. 2015. MicroRNA signatures differentiate Crohn’s disease from ulcerative colitis. BMC Immunology 16: 5.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Boomiraj, H., V. Mohankumar, P. Lalitha, and B. Devarajan. 2015. Human corneal microRNA expression profile in fungal keratitis. Investigative Ophthalmology & Visual Science 56: 7939–7946.

    Article  Google Scholar 

  30. Naqvi, A.R., J.B. Fordham, and S. Nares. 2015. miR-24, miR-30b, and miR-142-3p regulate phagocytosis in myeloid inflammatory cells. Journal of Immunology 194: 1916–1927.

    Article  CAS  Google Scholar 

  31. Yamada, Y., K. Kosaka, T. Miyazawa, K. Kurata-Miura, and T. Yoshida. 2014. miR-142-3p enhances FcepsilonRI-mediated degranulation in mast cells. Biochemical and Biophysical Research Communications 443: 980–986.

    Article  CAS  PubMed  Google Scholar 

  32. Sun, Y., S. Varambally, C.A. Maher, Q. Cao, P. Chockley, T. Toubai, C. Malter, E. Nieves, I. Tawara, Y. Wang, et al. 2011. Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood 117: 6172–6183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xiao, P., and W.L. Liu. 2015. MiR-142-3p functions as a potential tumor suppressor directly targeting HMGB1 in non-small-cell lung carcinoma. International Journal of Clinical and Experimental Pathology 8: 10800–10807.

    PubMed  PubMed Central  Google Scholar 

  34. Andersson, U., and K.J. Tracey. 2011. HMGB1 is a therapeutic target for sterile inflammation and infection. Annual Review of Immunology 29: 139–162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kang, R., R. Chen, Q. Zhang, W. Hou, S. Wu, L. Cao, J. Huang, Y. Yu, X.G. Fan, Z. Yan, et al. 2014. HMGB1 in health and disease. Molecular Aspects of Medicine 40: 1–116.

    Article  CAS  PubMed  Google Scholar 

  36. Terada, C., A. Yoshida, Y. Nasu, S. Mori, Y. Tomono, M. Tanaka, H.K. Takahashi, M. Nishibori, T. Ozaki, and K. Nishida. 2011. Gene expression and localization of high-mobility group box chromosomal protein-1 (HMGB-1) in human osteoarthritic cartilage. Acta Medica Okayama 65: 369–377.

    CAS  PubMed  Google Scholar 

  37. Ke, X., G. Jin, Y. Yang, X. Cao, R. Fang, X. Feng, and B. Lei. 2015. Synovial fluid HMGB-1 levels are associated with osteoarthritis severity. Clinical Laboratory 61: 809–818.

    CAS  PubMed  Google Scholar 

  38. Wahamaa, H., H. Schierbeck, H.S. Hreggvidsdottir, K. Palmblad, A.C. Aveberger, U. Andersson, and H.E. Harris. 2011. High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts. Arthritis Research and Therapy 13: R136.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Qin, Y., Y. Chen, W. Wang, Z. Wang, G. Tang, P. Zhang, Z. He, Y. Liu, S.M. Dai, and Q. Shen. 2014. HMGB1-LPS complex promotes transformation of osteoarthritis synovial fibroblasts to a rheumatoid arthritis synovial fibroblast-like phenotype. Cell Death & Disease 5: e1077.

    Article  CAS  Google Scholar 

  40. Guijarro-Munoz, I., M. Compte, A. Alvarez-Cienfuegos, L. Alvarez-Vallina, and L. Sanz. 2014. Lipopolysaccharide activates toll-like receptor 4 (TLR4)-mediated NF-kappaB signaling pathway and proinflammatory response in human pericytes. Journal of Biological Chemistry 289: 2457–2468.

    Article  CAS  PubMed  Google Scholar 

  41. Weber, D.J., A.S. Gracon, M.S. Ripsch, A.J. Fisher, B.M. Cheon, P.H. Pandya, R. Vittal, M.L. Capitano, Y. Kim, Y.M. Allette, et al. 2014. The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation. Science Translational Medicine 6: 252ra124.

    Article  PubMed  Google Scholar 

  42. Sun, J., S. Shi, Q. Wang, K. Yu, and R. Wang. 2015. Continuous hemodiafiltration therapy reduces damage of multi-organs by ameliorating of HMGB1/TLR4/NFkappaB in a dog sepsis model. International Journal of Clinical and Experimental Pathology 8: 1555–1564.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Record Room, Weihai Municipal Hospital, Weihai, 264200, China

    Xiuqin Wang

  2. Department of Traumatology and Arthrosis, Weihai Municipal Hospital, No. 70 Heping Road, Weihai, 264200, China

    Yanqing Guo, Hong Yu, Xiuxiang Yu & Hongbo Yu

  3. Operating Room, Weihai Municipal Hospital, Weihai, 264200, China

    Chunyan Wang

Authors
  1. Xiuqin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yanqing Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chunyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiuxiang Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongbo Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongbo Yu.

Ethics declarations

The animal use and experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committee of Weihai Municipal Hospital.

Conflict of Interest

The authors declare that they have no conflict of interest.

ELECTRONIC SUPPLEMENTARY MATERIAL

Below is the link to the electronic supplementary material.

Fig. S1

miR-142-3p has no effect on chondrocyte proliferation. Cells were transfected with miR-142-3p mimic or miR-NC for 48 h and then subjected to MTT detection. # p > 0.05 denotes no significant difference. (GIF 6 kb)

High resolution image (TIF 91 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Guo, Y., Wang, C. et al. MicroRNA-142-3p Inhibits Chondrocyte Apoptosis and Inflammation in Osteoarthritis by Targeting HMGB1. Inflammation 39, 1718–1728 (2016). https://doi.org/10.1007/s10753-016-0406-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-016-0406-3

KEY WORDS

Search

Navigation