Abstract
Osteoarthritis (OA) is a leading cause of joint deformity and functional limitation. An imbalance of anabolic and catabolic activity results in destruction of the extracellular matrix of articular cartilage. There is evidence to support the role of DNA methylation in the pathogenesis of OA, but the effect of other epigenetic modifiers is yet to be described. This study looks at the effect of novel epigenetic modulators, PFI-1, a bromodomain inhibitor, and SGC707, a histone methytransferase inhibitor, and their effects on gene expression in the pathogenesis of OA. Chondrocytes were extracted from OA femoral heads (n=6), cultured and incubated. Samples were treated with media alone (control), interleukin 1-beta (IL-1β) plus oncostatin M (OSM) alone, or in combination with increasing concentrations of PFI-1 or SGC707. Levels of expression of iNOS, COX2, IL8, IL1B, matrix metalloproteinase-13 (MMP13), RUNX2 and COL9A1 were measured using qRT-PCR, and expressed relative to GAPDH. PFI-1 (0.5 and 5µM) suppressed expression of catabolic genes in OA chondrocytes, at basal levels and when co-stimulated with IL-1β+OSM. Catabolic gene expression decreased (iNOS, COX2, IL-8, IL-1β and MMP), and RUNX2 expression was also supressed. There was no effect on expression of the anabolic gene COL9A1. SGC707 (0.1 and 1µM) did not induce a reduction in expression of all the catabolic genes. This study has demonstrated that PFI-1 has a potent protective effect against cartilage degradation, by modulating the expression of catabolic genes in OA chondrocytes. This further validates the role of epigenetics in OA, with implications for therapeutic interventions in the future.
