• Alexandra Jurczak, Lauriane Delay, Julie Barbier, Nils Simon, Emerson Krock, Katalin Sandor, Nilesh M Agalave, Resti Rudjito, Gustaf Wigerblad, Katarzyna Rogóż, Arnaud Briat, Elisabeth Miot-Noirault, Arisai Martinez-Martinez, Dieter Brömme, Caroline Grönwall, Vivianne Malmström, Lars Klareskog, Spiro Khoury, Thierry Ferreira, Bonnie Labrum, Emmanuel Deval, Jiménez-AndradeJuan MiguelJM0000-0002-2703-9736Unidad Academica Multidisciplinaria Reynosa Aztlan, Universidad Autonoma de Tamaulipas, Reynosa, Tamaulipas, Mexico., Fabien Marchand, and Camilla I Svensson.
• Department of Physiology and Pharmacology, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
• Pain. 2022 Aug 1; 163 (8): 154215591542-1559.

AbstractSeveral bone conditions, eg, bone cancer, osteoporosis, and rheumatoid arthritis (RA), are associated with a risk of developing persistent pain. Increased osteoclast activity is often the hallmark of these bony pathologies and not only leads to bone remodeling but is also a source of pronociceptive factors that sensitize the bone-innervating nociceptors. Although historically bone loss in RA has been believed to be a consequence of inflammation, both bone erosion and pain can occur years before the symptom onset. Here, we have addressed the disconnection between inflammation, pain, and bone erosion by using a combination of 2 monoclonal antibodies isolated from B cells of patients with RA. We have found that mice injected with B02/B09 monoclonal antibodies (mAbs) developed a long-lasting mechanical hypersensitivity that was accompanied by bone erosion in the absence of joint edema or synovitis. Intriguingly, we have noted a lack of analgesic effect of naproxen and a moderate elevation of few inflammatory factors in the ankle joints suggesting that B02/B09-induced pain-like behavior does not depend on inflammatory processes. By contrast, we found that inhibiting osteoclast activity and acid-sensing ion channel 3 signaling prevented the development of B02/B09-mediated mechanical hypersensitivity. Moreover, we have identified secretory phospholipase A2 and lysophosphatidylcholine 16:0 as critical components of B02/B09-induced pain-like behavior and shown that treatment with a secretory phospholipase A2 inhibitor reversed B02/B09-induced mechanical hypersensitivity and bone erosion. Taken together, our study suggests a potential link between bone erosion and pain in a state of subclinical inflammation and offers a step forward in understanding the mechanisms of bone pain in diseases such as RA.Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.

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