PT  - JOURNAL ARTICLE
AU  - Rachel E. Miller
AU  - Richard J. Miller
AU  - Shingo Ishihara
AU  - Phuong B. Tran
AU  - Suzanne B. Golub
AU  - Karena Last
AU  - Amanda J. Fosang
AU  - Anne-Marie Malfait
TI  - An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2
AID  - 10.1101/160432
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 160432
4099  - http://biorxiv.org/content/early/2017/07/07/160432.short
4100  - http://biorxiv.org/content/early/2017/07/07/160432.full
AB  - 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 ADAMTS-4/5-mediated cleavage in the interglobular domain (E373-374 A). Further cleavage by MMPs (N341-342 F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We demonstrated that the 32-mer excites dorsal root ganglion (DRG) nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced them to express the pro-algesic chemokine, MCP-1/CCL2. These effects were mediated through Toll-like receptor (TLR)2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer provoked knee hyperalgesia in wild-type 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.