TY - JOUR T1 - Targeting FoxO transcription factors with HDAC inhibitors for the treatment of osteoarthritis JF - Annals of the Rheumatic Diseases JO - Ann Rheum Dis SP - 262 LP - 271 DO - 10.1136/ard-2021-221269 VL - 82 IS - 2 AU - Hiroki Ohzono AU - Yiwen Hu AU - Keita Nagira AU - Haruhisa Kanaya AU - Naoki Okubo AU - Merissa Olmer AU - Masafumi Gotoh AU - Ichiro Kurakazu AU - Yukio Akasaki AU - Manabu Kawata AU - Emily Chen AU - Alan C Chu AU - Kristen A Johnson AU - Martin K Lotz Y1 - 2023/02/01 UR - http://ard.bmj.com/content/82/2/262.abstract N2 - Objectives Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4). The objective of this study was to identify small molecules that can increase FoxO1 expression.Methods We constructed a reporter cell line with FoxO1 promoter sequences and performed high-throughput screening (HTS) of the Repurposing, Focused Rescue and Accelerated Medchem (ReFRAME) library . Hits from the HTS were validated and function was assessed in human chondrocytes, meniscus cells and synoviocytes and following administration to mice. The most promising hit, the histone deacetylase inhibitor (HDACI) panobinostat was tested in a murine OA model.Results Among the top hits were HDACI and testing in human chondrocytes, meniscus cells and synoviocytes showed that panobinostat was the most promising compound as it increased the expression of autophagy genes and PRG4 while suppressing the basal and IL-1β induced expression of inflammatory mediators and extracellular matrix degrading enzymes. Intraperitoneal administration of panobinostat also suppressed the expression of mediators of OA pathogenesis induced by intra-articular injection of IL-1β. In a murine OA model, panobinostat reduced the severity of histological changes in cartilage, synovium and subchondral bone and improved pain behaviours.Conclusion Panobinostat has a clinically relevant activity profile and is a candidate for OA symptom and structure modification.Data sharing not applicable as no datasets generated and/or analysed for this study. ER -