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

Tieshi Li, Susan Chubinskaya, Alessandra Esposito, Xin Jin, Lidia Tagliafierro, Richard Loeser, Arnavaz A. Hakimiyan, Lara Longobardi, Huseyin Ozkan, Anna Spagnoli

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Article numbereaan2585
JournalScience translational medicine
Volume11
Issue number491
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Li, T., Chubinskaya, S., Esposito, A., Jin, X., Tagliafierro, L., Loeser, R., Hakimiyan, A. A., Longobardi, L., Ozkan, H., & Spagnoli, A. (2019). TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Science translational medicine, 11(491), [eaan2585]. https://doi.org/10.1126/scitranslmed.aan2585