Understanding CpG Methylation in the Context of Osteoarthritis

Abstract

Worldwide, osteoarthritis (OA) affects approxi‐ mately 40% of people older than 70 years and is therefore the most common form of arthritis. OA is a complex degenerative disease of the joint but is epitomized by focal degradation of articular cartilage [1]. Cartilage itself is a highly special‐ ized tissue composed of an extracellular matrix (ECM) rich in type‐II collagen and the proteo‐ glycan aggrecan. The tissue is sparsely populated by the sole resident cell, the chondrocyte, which maintains tissue integrity by balancing the syn‐ thesis and degradation of ECM components [2]. In OA, this balance is perturbed in favor of ECM degradation, mediated by proteolytic enzymes including MMP13 and ADAMTS5, which prob‐ ably degrade the type‐II collagen and aggrecan, respectively [3]. Inhibition of metalloproteinase activity should protect against cartilage destruc‐ tion, but has failed in clinical trials in part owing to nonselectivity and resulting adverse side effects [4]. Amongst other things, this has led to the sug‐ gestion that targeting the regulation of expression of specific proteases, or regulating factors, could be an important therapeutic option to slow or halt OA progression. There is an urgent need for such disease‐modifying, noninvasive treatments for OA since the only current therapy is joint replacement surgery. Epigenetic regulation involves three basic mechanisms: DNA methylation, histone modi‐ fications and ncRNAs. DNA methylation rep‐ resents the most stable epigenetic modification and involves the addition of a methyl group to the cytosine at CpG dinucleotides, converting cytosine to 5‐methylcytosine. This functions to disrupt the binding of transcription factors or enhance the binding of repressors, leading to an altered transcriptional state of the cell [5]. In terms of OA research, a number of studies have inves‐ tigated the role that epigenetics, especially DNA methylation, could play in OA, particularly in terms of regulating the balance between matrix synthesis and degradation in cartilage. These studies have focused on correlating DNA methyla‐ tion status with gene expression at a few candidate genes (loci), including those coding for aggrecan, collagens, MMPs, LEPTIN, SOX9 and RUNX2 [6]. Broadly, these works have shown a correlation between promoter methylation and the expression of the associated gene. Recently, we took this work one step further and identified a specific differen‐ tially methylated CpG locus within the MMP13 promoter whose methylation status regulates the expression of the gene by controlling the binding of the transcriptional regulator CREB [7]. These and ongoing ‘candidate’ gene studies will continue to identify differentially methylated regions that may be important in onset of the disease.