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AbstractOver 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 ALDH1A2, 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 ALDH1A2 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 ALDH1A2 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 in vivo 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 in vitro and in vivo, and identifies RAMBAs as potential disease modifying drugs in OA.One Sentence SummaryAnalysis of hand OA cartilage stratified by ALDH1A2 polymorphic variants reveals a targetable, anti-inflammatory role for retinoic acid in OA.

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