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 journalArticlepeer-review

47 Scopus citations


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
Issue number491
StatePublished - 2019
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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