Research ArticleOsteoarthritis

TGF-β type 2 receptor–mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaan2585
DOI: 10.1126/scitranslmed.aan2585

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Joy for joints

Disease-modifying drugs are lacking for osteoarthritis (OA), a disease due to cartilage erosion in joints. Li et al. used multiple mouse models and samples from patients with OA to discern cytokine pathways involved in the development of disease. Heightened IL-36 was detected during joint destruction, and TGFBR2 signaling in healthy joints dampened IL-36 signaling. TGF-β inhibition would have widespread effects, so the authors focused on the IL-36 family as a target. Injection of an IL-36 receptor antagonist into mouse knees ameliorated OA. The IL-36 receptor antagonist also prevented secretion of damaging metalloproteases from human chondrocytes in vitro. These findings suggest that targeting IL-36 signaling may bring relief for patients suffering from OA.

Abstract

Mechanisms that govern the shift from joint homeostasis to osteoarthritis (OA) remain unknown. Here, we identify a pathway used for joint development and homeostasis, and its role in OA. Using a combination of transgenic, pharmacological, and surgical conditions in mouse and human tissues, we found that TGF-β signaling promotes joint homeostasis through regulation of the IL-36 family. We identified IL-36 receptor antagonist (IL-36 in mice and IL-36RN in humans) as a potential disease-modifying OA drug. Specifically, OA development was associated with IL-36α up-regulation and IL-36Ra down-regulation in mice with tissue-specific postnatally induced ablation of Tgfbr2, mice treated with a TGF-β signaling inhibitor, mice with posttraumatic OA, and aging mice with naturally occurring OA. In human cartilage, OA severity was associated with decreased TGFBR2 and IL-36RN, whereas IL-36α increased. Functionally, intra-articular treatment with IL-36Ra attenuated OA development in mice, and IL-36RN reduced MMP13 in human OA chondrocytes. These findings highlight the relevance of TGFBR2–IL-36 interplay in joint homeostasis and IL-36RN as a potential therapeutic agent for OA.

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