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

2 Citations (Scopus)

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 - Jan 1 2019

Fingerprint

Osteoarthritis
Homeostasis
Joints
Chondrocytes
Cartilage
Up-Regulation
Down-Regulation
Pharmacology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. / Li, Tieshi; Chubinskaya, Susan; Esposito, Alessandra; Jin, Xin; Tagliafierro, Lidia; Loeser, Richard; Hakimiyan, Arnavaz A.; Longobardi, Lara; Ozkan, Huseyin; Spagnoli, Anna.

In: Science translational medicine, Vol. 11, No. 491, eaan2585, 01.01.2019.

Research output: Contribution to journalArticle

Li, T, Chubinskaya, S, Esposito, A, Jin, X, Tagliafierro, L, Loeser, R, Hakimiyan, AA, 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, vol. 11, no. 491, eaan2585. https://doi.org/10.1126/scitranslmed.aan2585
Li, Tieshi ; Chubinskaya, Susan ; Esposito, Alessandra ; Jin, Xin ; Tagliafierro, Lidia ; Loeser, Richard ; Hakimiyan, Arnavaz A. ; Longobardi, Lara ; Ozkan, Huseyin ; Spagnoli, Anna. / TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. In: Science translational medicine. 2019 ; Vol. 11, No. 491.
@article{4e24c6b7ba5c4393a1205adba27e83a6,
title = "TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis",
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.",
author = "Tieshi Li and Susan Chubinskaya and Alessandra Esposito and Xin Jin and Lidia Tagliafierro and Richard Loeser and Hakimiyan, {Arnavaz A.} and Lara Longobardi and Huseyin Ozkan and Anna Spagnoli",
year = "2019",
month = "1",
day = "1",
doi = "10.1126/scitranslmed.aan2585",
language = "English (US)",
volume = "11",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "491",

}

TY - JOUR

T1 - TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis

AU - Li, Tieshi

AU - Chubinskaya, Susan

AU - Esposito, Alessandra

AU - Jin, Xin

AU - Tagliafierro, Lidia

AU - Loeser, Richard

AU - Hakimiyan, Arnavaz A.

AU - Longobardi, Lara

AU - Ozkan, Huseyin

AU - Spagnoli, Anna

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065801403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85065801403&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aan2585

DO - 10.1126/scitranslmed.aan2585

M3 - Article

C2 - 31068441

AN - SCOPUS:85065801403

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 491

M1 - eaan2585

ER -