The role of retinoic acid in cartilage mechanoflammation

Thesis

Osteoarthritis (OA) is a highly prevalent condition that affects more than 40% of individuals over the course of their lifetime. There are currently no disease-modifying OA drug (DMOAD) licensed for the treatment of this disease. An Icelandic genome wide association study (GWAS) study identified common polymorphic variants in ALDH1A2, the gene which encodes the enzyme involved in the synthesis of all-trans retinoic acid (atRA), with severe hand OA. Subsequent data from our lab showed that atRA-responsive genes are downregulated on cartilage injury. Mechanical injury is one of the principal risk factors in the development of OA. Cartilage injury is known to activate downstream inflammatory signalling that is driven in a transforming growth factor activated-beta 1 (TAK1) dependent manner and thereby increase inflammatory gene regulation, in a process known as mechanoflammation. Talarozole (TLZ), a CYP26 inhibitor, which prevents the breakdown of atRA, suppresses the upregulation of inflammatory genes on cartilage injury. My project sought to identify the mechanism by which atRA-responsive genes were downregulated and determine how atRA suppressed mechanoflammation on cartilage injury. The downregulation of atRA-responsive genes on cartilage injury was mediated in both cytosolic phospholipase A2 (cPLA2) - and reactive oxygen species (ROS)-sensitive manner. TAK1 phosphorylation on cartilage injury was partially mediated in a nicotinamide adenine dinucleotide phosphate oxidase (NOX)-sensitive manner, whereas TAK1 was responsible for the partial phosphorylation of cPLA2 on cartilage injury. Apoptosis signal regulating kinase 1 (ASK1) was the key driver of mitogen activated protein kinases (MAPKs) (Jun N terminal kinase (JNK) and extracellular signal regulated kinase (ERK)) on cartilage injury and downstream inflammatory gene regulation. atRA suppressed mechanoflammation in a peroxisome proliferator activated receptor gamma (PPARG)-sensitive manner. These findings suggest that both boosting atRA level and ASK1 inhibition can suppress mechanoflammation in articular cartilage and identifies each pathway as targets for potential disease modifying drugs in the treatment of OA.

Authors: Kamalathevan, P

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: inflammation; cartilage; osteoarthritis; retinoic acid
• Subjects: Cartilage; Osteoarthritis; Inflammation