@article{10.1172/jci.insight.95704, author = {Rachel E. Miller AND Shingo Ishihara AND Phuong B. Tran AND Suzanne B. Golub AND Karena Last AND Richard J. Miller AND Amanda J. Fosang AND Anne-Marie Malfait}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2}, year = {2018}, month = {3}, volume = {3}, url = {https://insight.jci.org/articles/view/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.}, number = {6}, doi = {10.1172/jci.insight.95704}, url = {https://doi.org/10.1172/jci.insight.95704}, }