Imperial College London
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DrFionaWatt

Faculty of Medicine, Department of Immunology and Inflammation

Reader in Rheumatology
 
 
 
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f.watt

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@unpublished{Zhu:2021:10.1101/2021.09.10.457848,
author = {Zhu, L and Kamalathevan, P and Koneva, L and Zarebska, JM and Chanalaris, A and Ismail, H and Wiberg, A and Ng, M and Muhammed, H and Watt, FE and Sansom, S and Furniss, D and Gardiner, MD and Vincent, TL},
doi = {10.1101/2021.09.10.457848},
title = {Variants in<i>ALDH1A2</i>reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis},
url = {http://dx.doi.org/10.1101/2021.09.10.457848},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - UNPB
AB  - <jats:title>Abstract</jats:title><jats:p>Over 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease modifying treatments for this disabling condition. Common polymorphic variants in<jats:italic>ALDH1A2</jats:italic>, that encodes the key enzyme in the synthesis of all-trans retinoic acid (atRA), have been associated with severe hand OA. In this study, we sought to elucidate the biological significance of this association. We first confirmed that<jats:italic>ALDH1A2</jats:italic>risk variants were associated with hand OA in UK Biobank. Articular cartilage was acquired from 33 consenting individuals with hand OA at the time of routine hand OA surgery. They were stratified by genotype and RNA sequencing performed. A reciprocal relationship between<jats:italic>ALDH1A2</jats:italic>mRNA and inflammatory genes was observed. Articular cartilage injury up-regulates similar inflammatory genes by a process that we have previously termed mechanoflammation, and which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-dependent genes, indicative of cellular atRA levels, and both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator activated receptor (PPAR)-γ dependent mechanism. Talarozole, delivered by minipump, was able to suppress mechano-inflammatory genes in articular cartilage<jats:italic>in vivo</jats:italic>6h after mouse knee joint destabilization, and reduced cartilage degradation and osteophyte formation after 4 weeks. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage<jats:italic>in vitro</jats:italic>and<jats:italic>in vivo</jats:italic>, and identifies RAMBAs as potential dise
AU  - Zhu,L
AU  - Kamalathevan,P
AU  - Koneva,L
AU  - Zarebska,JM
AU  - Chanalaris,A
AU  - Ismail,H
AU  - Wiberg,A
AU  - Ng,M
AU  - Muhammed,H
AU  - Watt,FE
AU  - Sansom,S
AU  - Furniss,D
AU  - Gardiner,MD
AU  - Vincent,TL
DO  - 10.1101/2021.09.10.457848
PY  - 2021///
TI  - Variants in<i>ALDH1A2</i>reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis
UR  - http://dx.doi.org/10.1101/2021.09.10.457848
ER  -
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