Toll-like receptor adaptor signaling molecule MyD88 on intervertebral disk homeostasis: In vitro, ex vivo studies

Michael B. Ellman, Jae Sung Kim, Howard S. An, Di Chen, Ranjan KC, Jennifer An, Teju Dittakavi, Andre J van Wijnen, Gabriella Cs-Szabo, Xin Li, Guozhi Xiao, Steven An, Su Gwan Kim, Hee Jeong Im

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

MyD88 is an adapter protein that links toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs) with downstream signaling molecules. The MyD88 has been found to be an essential mediator in the development of osteoarthritis in articular cartilage. However, the role of the MyD88 pathway has yet to be elucidated in the intervertebral disk (IVD). Using in vitro techniques, we analyzed the effect of MyD88 pathway-specific inhibition on the potent inflammatory and catabolic mediator LPS and IL-1 in bovine and human nucleus pulposus (NP) cells by assessing matrix-degrading enzyme expression, including matrix metalloproteases (MMPs) and a disintegrin-like and metalloprotease with thrombospondin motifs (ADAMTS family). We also analyzed inhibition of MyD88 in the regulation of inducible nitric oxide synthase and TLR-2. Finally, we used an ex vivo organ culture model to assess the effects of MyD88 inhibitor (MyD88. i) on catabolic factor-induced disk degeneration in mice lumbar disks. In bovine NP cells, MyD88. i potently antagonizes LPS- or IL-1-mediated induction of cartilage-degrading enzyme production, including MMP-1, MMP-13, ADAMTS-4, and ADAMTS-5. MyD88. i also attenuates the LPS- or IL-1-mediated induction of iNOS and TLR-2 gene expression. Our ex vivo findings reveal inhibition of MyD88 via counteraction of IL-1-mediated proteoglycan depletion. The findings from this study demonstrate the potent anti-inflammatory and anti-catabolic effects of inhibition of MyD88 pathway inhibition on IVD homeostasis, suggesting a potential therapeutic benefit of a MyD88. i in degenerative disk disease in the future.

Original languageEnglish (US)
Pages (from-to)283-290
Number of pages8
JournalGene
Volume505
Issue number2
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

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Keywords

  • Intervertebral disk degeneration
  • Low back pain
  • MyD88 inhibitor
  • Signaling pathway
  • Toll-like receptors

ASJC Scopus subject areas

  • Genetics

Cite this

Ellman, M. B., Kim, J. S., An, H. S., Chen, D., KC, R., An, J., Dittakavi, T., van Wijnen, A. J., Cs-Szabo, G., Li, X., Xiao, G., An, S., Kim, S. G., & Im, H. J. (2012). Toll-like receptor adaptor signaling molecule MyD88 on intervertebral disk homeostasis: In vitro, ex vivo studies. Gene, 505(2), 283-290. https://doi.org/10.1016/j.gene.2012.06.004