Genome-Wide Association Studies to Drug: Identifying Retinoic Acid Metabolism Blocking Agents to Suppress Mechanoflammation in Osteoarthritis.

Osteoarthritis (OA) is a highly prevalent debilitating joint disease for which there are currently no licensed disease-modifying treatments. The pathogenesis of OA is complex, involving genetic, mechanical, biochemical, and environmental factors. Cartilage injury, arguably the most important driving factor in OA development, is able to activate both protective and inflammatory pathways within the tissue. Recently, >100 genetic risk variants for OA have been identified through Genome Wide Association Studies, which provide a powerful tool to validate existing putative disease pathways and discover new ones. Using such an approach, hypomorphic variants within the aldehyde dehydrogenase 1 family member A2 ( ALDH1A2 ) gene were shown to be associated with increased risk of severe hand OA. ALDH1A2 encodes the enzyme that synthesizes all-trans retinoic acid (atRA), an intracellular signaling molecule. This review summarizes the influence of the genetic variants on expression and function of ALDH1A2 in OA cartilage, its role in the mechanical injury response of cartilage, and its potent anti-inflammatory effect after cartilage injury. In doing so it identifies atRA metabolism-blocking agents as potential treatments for suppressing mechanoflammation in OA.