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

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

Author information

1
Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, Chicago, Illinois, USA.
2
University of Melbourne Department of Paediatrics, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
3
Department of Pharmacology, Northwestern University, Chicago, Illinois, USA.

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

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