An Aggrecan Fragment Drives Osteoarthritis Pain Through Toll-like Receptor 2

JCI Insight. 2018 Mar 22;3(6):e95704. doi: 10.1172/jci.insight.95704.

Abstract

Pain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by cleavage mediated by a disintegrin and metalloproteinase with thrombospondin motif 4 (ADAMTS-4) or ADAMTS-5 in the interglobular domain (E373-374A). Further cleavage by MMPs (N341-342F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We found that the 32-mer excites dorsal root ganglion nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced expression of the proalgesic chemokine CCL2. These effects were mediated through TLR2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer fragment provoked knee hyperalgesia in WT but not Tlr2-null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.

Keywords: Bone Biology; Extracellular matrix; Neuroscience; Osteoarthritis; Pain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS4 Protein / metabolism
  • ADAMTS5 Protein / metabolism
  • Aggrecans / metabolism*
  • Animals
  • Arthralgia / metabolism*
  • Calcium / metabolism
  • Cartilage, Articular / metabolism
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • Ganglion Cysts / metabolism
  • Matrix Metalloproteinases
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Osteoarthritis / genetics
  • Osteoarthritis / metabolism*
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*

Substances

  • Aggrecans
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • ADAMTS5 Protein
  • Matrix Metalloproteinases
  • ADAMTS4 Protein
  • Calcium