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Interleukin-6 signaling mediates cartilage degradation and pain in posttraumatic osteoarthritis in a sex-specific manner

Yihan Liao,Yinshi Ren,Xin Luo,A. Mirando,Jason T. Long,Abigail P. Leinroth,R. Ji,M. Hilton

Published 2022 in Science Signaling

ABSTRACT

Osteoarthritis (OA) and posttraumatic OA (PTOA) are caused by an imbalance in catabolic and anabolic processes in articular cartilage and proinflammatory changes throughout the joint, leading to joint degeneration and pain. We examined whether interleukin-6 (IL-6) signaling contributed to cartilage degradation and pain in PTOA. Genetic ablation of Il6 in male mice decreased PTOA-associated cartilage catabolism, innervation of the knee joint, and nociceptive signaling without improving PTOA-associated subchondral bone sclerosis or chondrocyte apoptosis. These effects were not observed in female Il6−/− mice. Compared with wild-type mice, the activation of the IL-6 downstream mediators STAT3 and ERK was reduced in the knees and dorsal root ganglia (DRG) of male Il6−/− mice after knee injury. Janus kinases (JAKs) were critical for STAT and ERK signaling in cartilage catabolism and DRG pain signaling in tissue explants. Whereas STAT3 signaling was important for cartilage catabolism, ERK signaling mediated neurite outgrowth and the activation of nociceptive neurons. These data demonstrate that IL-6 mediates both cartilage degradation and pain associated with PTOA in a sex-specific manner and identify tissue-specific contributions of downstream effectors of IL-6 signaling, which are potential therapeutic targets for disease-modifying OA drugs. Description IL-6 drives joint degeneration and pain in osteoarthritis in male mice, but not in female mice. A painful breakdown of cartilage The proinflammatory cytokine interleukin-6 (IL-6) is associated with structural changes in joints that characterize osteoarthritis (OA) and with inflammatory pain. Using a model of injury-induced OA, Liao et al. demonstrated that IL-6 promoted both disease symptoms in a sex-specific manner (see the Focus by Pacifici). In male mice, IL-6 promoted articular cartilage degeneration through the kinase JAK and the downstream effector STAT3, whereas it promoted joint innervation and pain signaling through the JAK downstream effector ERK. These findings have implications for potential sex-specific OA therapies.

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