Most advanced knee osteoarthritis (OA) patients experience chronic pain resistant to cyclooxygenase (COX) inhibitors. However, the cells and molecules involved in this advanced OA pain remain poorly understood. In this study, we developed a rat model of advanced knee OA by modification of the monoiodoacetate-induced OA pain model and examined involvement of synovial macrophages in advanced OA pain. Cyclooxygenase inhibitors, such as celecoxib and naproxen, and a steroid were ineffective, but an opioid and anti–nerve growth factor (NGF) antibody was effective for pain management in the advanced OA model. Similar to advanced OA patients, histological analysis indicated severe bone marrow damages, synovitis, and cartilage damage and an increase of macrophages with high expression of interleukin-1β, NGF, nitric oxide synthase (NOS) 1, NOS2, and COX-2 in the knee joint of the advanced OA model. Intravenous injection of clodronate liposomes depleted synovial macrophages, which decreased the level of not only proinflammatory mediator interleukin-1β but also NGF in the knee joint, leading to pain suppression in the advanced OA model. These data suggest the involvement of synovial macrophages in advanced knee OA pain resistant to COX inhibitors by increasing proinflammatory mediators, and that drugs targeting synovial macrophages might have potent analgesic effects.
Synovial macrophages contributed to joint pain resistant to cyclooxygenase inhibitors in rat advanced osteoarthritis model through increase of proinflammatory mediators in the knee joint.
aNeuroscience, Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan
bInfectious Diseases and Immunology, Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan
cTranslational Research Unit, Biomarker R&D Department, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan
dInfectious diseases & Microbiology, Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan
Corresponding author. Address: Neuroscience, Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan. Tel.: +81-6-6331-6609; fax: +81-6-6332-6385. E-mail address: email@example.com (Y. Morioka).
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Received April 13, 2018
Received in revised form December 04, 2018
Accepted December 09, 2018