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An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2

Rachel E Miller1, Shingo Ishihara1, Phuong B Tran1

  • 1Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, Chicago, Illinois, USA.

JCI Insight
|March 23, 2018
PubMed

Insights

Osteoarthritis pain is linked to a specific aggrecan fragment (32-mer). This fragment activates pain-sensing neurons via TLR2, driving joint pain and hyperalgesia in osteoarthritis models.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Immunology

Background:

  • Osteoarthritis (OA) pain is a primary symptom, but its link to joint damage remains unclear.
  • Articular cartilage degradation in OA involves aggrecan cleavage by ADAMTS-4/5 and MMPs, releasing a 32-amino-acid fragment (32-mer).

Purpose of the Study:

  • To investigate the role of the aggrecan 32-mer fragment in the development of osteoarthritis-associated joint pain.
  • To elucidate the mechanism by which the 32-mer fragment contributes to OA pain.

Main Methods:

  • Cultured dorsal root ganglion (DRG) nociceptive neurons and intact explants were used to assess neuronal excitation by the 32-mer.
  • Expression of Toll-like receptor 2 (TLR2) on nociceptive neurons was confirmed.
  • Intra-articular injections of the 32-mer were performed in wild-type (WT) and Tlr2-null mice to evaluate hyperalgesia.
  • Blocking 32-mer production or action in transgenic mice assessed its role in an OA model.

Main Results:

  • The 32-mer fragment was found to excite DRG nociceptive neurons in vitro and in explants.
  • Treatment with the 32-mer induced CCL2 expression in sensory neurons, mediated via TLR2.
  • Intra-articular injection of the 32-mer caused knee hyperalgesia in WT mice, but not in Tlr2-null mice.
  • Inhibition of 32-mer production or action prevented knee hyperalgesia in a murine OA model.

Conclusions:

  • The aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors.
  • The 32-mer fragment is a key mediator in the development of osteoarthritis-associated joint pain.
Keywords:
Bone BiologyExtracellular matrixNeuroscienceOsteoarthritisPain

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