MAINTAINING ALL-TRANS RETINOIC ACID LEVELS WITH TALAROZOLE SUPPRESSES MECHANFLAMMATION FOLLOWING CARTILAGE INJURY THROUGH A PERIXOSOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA-DEPENDENT MECHANISM

Abstract

Purpose: Severe hand osteoarthritis (OA) is associated with polymorphic variants in the ALDH1A2 gene. ALDH1A2 encodes the enzyme that catalyses the rate limiting step in the synthesis of all-trans retinoic acid (atRA). Injury of porcine articular cartilage, by explantation, causes upregulation of inflammatory genes by a process we have termed “mechanoflammation”. Injury also causes a rapid drop in atRA-responsive genes suggesting that atRA levels within the cell drop upon injury. If levels of atRA are maintained using talarozole, a retinoic acid metabolism blocking agent (RAMBA), this inhibits the mechano-inflammatory response.