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Hyaluronic acid fragments enhance the inflammatory and catabolic response in human intervertebral disc cells through modulation of toll-like receptor 2 signalling pathways

Lilian Quero12, Marina Klawitter3, Anja Schmaus4, Melanie Rothley4, Jonathan Sleeman45, André N Tiaden3, Juergen Klasen6, Norbert Boos12, Michael O Hottiger7, Karin Wuertz1289 and Peter J Richards38*

Author Affiliations

1 Spine Research Group, CABMM, University of Zürich, Winterthurerstrasse 190, Zürich 8057, Switzerland

2 AOSpine Research Network, Stettbachstrasse 6, Duebendorf 8600, Switzerland

3 Bone and Stem Cell Research Group, CABMM, University of Zürich, Winterthurerstrasse 190, Zürich 8057, Switzerland

4 Karlsruher Institut für Technologie (KIT), Hermann-von-Helmholtz-Platz 1, Eggenstein-Leopoldshafen 76344, Germany

5 Universitätsmedizin Mannheim, University of Heidelberg, Centre for Biomedicine and Medical Technology Mannheim (CBTM), Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany

6 University Hospital Balgrist, Centre for Spinal Surgery, Forchstrasse 340, Zürich 8008, Switzerland

7 Institute of Veterinary Biochemistry and Molecular Biology, University of Zürich, Winterthurerstrasse 190, Zürich 8057, Switzerland

8 Zurich Centre for Integrative Human Physiology (ZIHP), University of Zürich, Winterthurerstrasse 190, Zürich 8057, Switzerland

9 Institute for Biomechanics, Swiss Federal Institute of Technology (ETH), Wolfgang-Pauli-Strasse 10, Zürich 8093, Switzerland

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Arthritis Research & Therapy 2013, 15:R94  doi:10.1186/ar4274

Published: 22 August 2013



Intervertebral disc (IVD) degeneration is characterized by extracellular matrix breakdown and is considered to be a primary cause of discogenic back pain. Although increases in pro-inflammatory cytokine levels within degenerating discs are associated with discogenic back pain, the mechanisms leading to their overproduction have not yet been elucidated. As fragmentation of matrix components occurs during IVD degeneration, we assessed the potential involvement of hyaluronic acid fragments (fHAs) in the induction of inflammatory and catabolic mediators.


Human IVD cells isolated from patient biopsies were stimulated with fHAs (6 to 12 disaccharides) and their effect on cytokine and matrix degrading enzyme production was assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The involvement of specific cell surface receptors and signal transduction pathways in mediating the effects of fHAs was tested using small interfering RNA (siRNA) approaches and kinase inhibition assays.


Treatment of IVD cells with fHAs significantly increased mRNA expression levels of interleukin (IL)-, IL-6, IL-8, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-1 and -13. The stimulatory effects of fHAs on IL-6 protein production were significantly impaired when added to IVD cells in combination with either Toll-like receptor (TLR)-2 siRNA or a TLR2 neutralizing antibody. Furthermore, the ability of fHAs to enhance IL-6 and MMP-3 protein production was found to be dependent on the mitogen-activated protein (MAP) kinase signaling pathway.


These findings suggest that fHAs may have the potential to mediate IVD degeneration and discogenic back pain through activation of the TLR2 signaling pathway in resident IVD cells.