The Emerging Role of Epigenetics in Rheumatic Diseases
The Emerging Role of Epigenetics in Rheumatic Diseases
The underlying pathogenic mechanisms of OA are poorly understood but involve genetic and environmental factors. Studies of the role of the epigenome have concentrated on chondrocytes. Genomic DNA methylation levels were found to be similar in chondrocytes from 10 OA and 10 normal joints, however, the levels of methylation of the leptin promoter were lower in chondrocytes isolated from severely involved cartilage compared with minimally involved or normal cartilage and were associated with greater expression of this catabolic cytokine and its downstream target MMP (MMP-3); similar findings have been reported in MMP-9, MMP-13 and ADAMTS (a disintegrin and metalloproteinase with a thrombospondin type 1 motif). Of particular note is the finding of lower ADAMTS-4 promoter methylation and higher expression in lesional compared with non-lesional chondrocytes. Nitric oxide (NO), a key signalling molecule, is produced at high levels by activated chondrocytes and mediates IL-1β-induced suppression of cartilage proteoglycan synthesis. Lesional chondrocytes express high levels of inducible NO synthesis (iNOS) and have reduced methylation of a nuclear factor κB (NF-κB) enhancer element 5.8 kb upstream of the iNOS transcriptional start site. These studies reveal the importance of comparing the epigenetic profiles of chondrocytes from lesional and non-lesional cartilage within the same OA joint.
Epigenetic Influences in OA
The underlying pathogenic mechanisms of OA are poorly understood but involve genetic and environmental factors. Studies of the role of the epigenome have concentrated on chondrocytes. Genomic DNA methylation levels were found to be similar in chondrocytes from 10 OA and 10 normal joints, however, the levels of methylation of the leptin promoter were lower in chondrocytes isolated from severely involved cartilage compared with minimally involved or normal cartilage and were associated with greater expression of this catabolic cytokine and its downstream target MMP (MMP-3); similar findings have been reported in MMP-9, MMP-13 and ADAMTS (a disintegrin and metalloproteinase with a thrombospondin type 1 motif). Of particular note is the finding of lower ADAMTS-4 promoter methylation and higher expression in lesional compared with non-lesional chondrocytes. Nitric oxide (NO), a key signalling molecule, is produced at high levels by activated chondrocytes and mediates IL-1β-induced suppression of cartilage proteoglycan synthesis. Lesional chondrocytes express high levels of inducible NO synthesis (iNOS) and have reduced methylation of a nuclear factor κB (NF-κB) enhancer element 5.8 kb upstream of the iNOS transcriptional start site. These studies reveal the importance of comparing the epigenetic profiles of chondrocytes from lesional and non-lesional cartilage within the same OA joint.
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