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

• DOI: 10.1172/jci.insight.95704
• Publication Date: 2018-03-21T15:01:17Z
• Authors: Rachel E. Miller; Shingo Ishihara; Phuong B. Tran; Suzanne B. Golub; Karena Last; Richard J. Miller; Amanda J. Fosang; Anne-Marie Malfait
• Keywords: Cartilage, Articular; Ganglion Cysts; Mice, Knockout; 0301 basic medicine; 0303 health sciences; 610; Mice, Transgenic; Arthralgia; Matrix Metalloproteinases; Toll-Like Receptor 2; Disease Models, Animal; Mice; 03 medical and health sciences; Osteoarthritis; ADAMTS4 Protein; Animals; Calcium; ADAMTS5 Protein; Aggrecans; 10. No inequality; Chemokine CCL2

AbstractPain 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 (E373-374A). 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 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 notTlr2null 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.