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

Rachel E. Miller, Richard J. Miller, Shingo Ishihara, Phuong B. Tran, Suzanne B. Golub, Karena Last, Amanda J. Fosang, Anne-Marie Malfait
doi: https://doi.org/10.1101/160432
Rachel E. Miller
1Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612
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Richard J. Miller
2Department of Pharmacology, Northwestern University, Chicago, IL
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Shingo Ishihara
1Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612
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Phuong B. Tran
1Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612
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Suzanne B. Golub
3University of Melbourne Department of Paediatrics, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
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Karena Last
3University of Melbourne Department of Paediatrics, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
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Amanda J. Fosang
3University of Melbourne Department of Paediatrics, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
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Anne-Marie Malfait
1Department of Internal Medicine, Division of Rheumatology, Rush University Medical Center, 1611 W. Harrison St, Suite 510, Chicago, IL 60612
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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 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.

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  • The authors have declared that no conflict of interest exists.

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Posted July 07, 2017.
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An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2
Rachel E. Miller, Richard J. Miller, Shingo Ishihara, Phuong B. Tran, Suzanne B. Golub, Karena Last, Amanda J. Fosang, Anne-Marie Malfait
bioRxiv 160432; doi: https://doi.org/10.1101/160432
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An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2
Rachel E. Miller, Richard J. Miller, Shingo Ishihara, Phuong B. Tran, Suzanne B. Golub, Karena Last, Amanda J. Fosang, Anne-Marie Malfait
bioRxiv 160432; doi: https://doi.org/10.1101/160432

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