DNA methylation and osteoarthritis

Abstract

Osteoarthritis is a debilitating and progressive disease that affects around two-thirds of people of retirement age. A key feature is the degradation of articular cartilage, leading to loss of shock-absorbing capacity, pain, and difficulties in articulation of the joints. The enzymes involved in the cartilage degradation are, paradoxically, produced by the chondrocytes, which undergo a phenotypic change from normal chondrocytes, which express the typical chondrocytic genes (collagens type II, IX, and XI, aggrecan, Sox-9, etc.), to cells that aberrantly express cartilage matrix-degrading proteases and other genes that are not part of the normal repertoire of chondrocytes. This chapter evaluates the evidence that DNA de-methylation at critical CpG sites in the relevant promoters underlies the aberrant expression of non-chondrocytic genes. Although definitive data are still limited, evidence is presented that the aberrant expression of MMP-3, MMP-9, MMP-13, ADAMTS-4, and leptin is associated with loss of CpG methylation. Another feature of osteoarthritis is the silencing of many genes that are expressed by normal chondrocytes. This does not seem to be connected to hyper-methylation of the CpG island promoters of type II collagen, aggrecan or p21WAF1/CIP1 (an inhibitor of proliferation), although there is some evidence that hyper-methylation might contribute to the silencing of osteogenic protein-1, an anabolic factor for cartilage. Further work is urgently needed to investigate not only the CpG methylation status of other genes that are induced or silenced in osteoarthritis but also the mechanisms involved in the loss of methylation and the factors that might initiate this loss.