| Autor: |
Zhu, Linyi, Kamalathevan, Pragash, Koneva, Lada A., Zarebska, Jadwiga Miotla, Chanalaris, Anastasios, Ismail, Heba, Wiberg, Akira, Ng, Michael, Muhammad, Hayat, Walsby-Tickle, John, McCullagh, James S.O., Watt, Fiona E., Sansom, Stephen N., Furniss, Dominic, Gardiner, Matthew D., Vincent, Tonia L., Riley, Nick, Spiteri, Michelle, McNab, Ian, Little, Christopher |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 12/21/2022, Vol. 14 Issue 676, p1-14, 14p |
| Abstrakt: |
More than 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, which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that ALDH1A2 risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between ALDH1A2 mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. 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 gamma (PPARγ)–dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. 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 for OA. Keeping osteoarthritis from getting out of hand: Keeping osteoarthritis from getting out of handOsteoarthritis (OA) is a debilitating medical condition with no treatments currently available. Here Zhu et al. identify variants in the ALDH1A2 gene, responsible for the synthesis of all-trans retinoic acid (atRA), in patients with severe hand OA and link risk alleles to cartilage injury and inflammation. They then show that administration of a retinoic acid metabolism blocking agent (RAMBA), talarozole, reduced cartilage injury and inflammation through a peroxisome proliferator–activated receptor gamma (PPARγ)–dependent mechanism in both mouse and pig joints in vivo and ex vivo, respectively. These results implicate atRA in the development of OA and suggest that RAMBAs may be a viable therapeutic option for the treatment of this disease. —AW [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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