Matrix Metalloproteinase Gene Activation Resulting from Disordred Epigenetic Mechanisms in Rheumatoid Arthritis

Abstract

Matrix metalloproteinases (MMPs) are implicated in the degradation of extracellular matrix (ECM). Rheumatoid arthritis (RA) synovial fibroblasts (SFs) produce matrix-degrading enzymes, including MMPs, which facilitate cartilage destruction in the affected joints in RA. Epigenetic mechanisms contribute to change in the chromatin state, resulting in an alteration of gene transcription. Recently, MMP gene activation has been shown to be caused in RASFs by the dysregulation of epigenetic changes, such as histone modifications, DNA methylation, and microRNA (miRNA) signaling. In this paper, we review the role of MMPs in the pathogenesis of RA as well as the disordered epigenetic mechanisms regulating MMP gene activation in RASFs.

Keywords: epigenetics; gene transcription; matrix metalloproteinase; rheumatoid arthritis.

Figure 1

Matrix metalloproteinases (MMPs) are comprised of different subdomains. Most have a minimal domain (a signal peptide, propeptide, and catalytic domain), a hinge region, and a hemopexin-like C-terminal domain. Gelatinases (MMP-2 and MMP-9) contain three repeats of a fibronectin type II motif in the catalytic domain. Membrane-type MMPs have a type I transmembrane domain/cytoplasmic domain or a glycosylphosphatidylinositol (GPI) anchor in addition. MMP-23 contains a type II transmembrane domain, a cysteine array, and an immunoglobulin-like domain. The propeptide contains a furin cleavage site (RXKR motif) in MMP-11, MMP-21, MMP-23, MMP-28, and membrane-type MMPs. MMP-7 and MMP-26 lack both a hinge region and a hemopexin-like C-terminal domain.

Figure 2

Histone modifications, including methylation, acetylation, ubiquitination, phosphorylation, and sumoylation have a variety of biological functions, including the regulation of chromatin states and gene transcription.

Figure 3

DNA methylation and demethylation are catalyzed by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, respectively. Cytosine at CpG sites is methylated by DNMTs to yield 5-methylcytosine (5mC). The 5mC is hydroxylated by TET enzymes to yield 5-hydroxymethylcytosine (5hmC), which in turn is oxidized to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The 5fC and 5caC are converted to unmethylated C by thymine DNA glycosylate (TDG)-mediated base excision repair.

Figure 4

MicroRNAs (miRNAs) are initially transcribed as long primary miRNA (pri-miRNA) and cleaved by Drosha to yield a short precursor miRNA (pre-miRNA) in the nucleus. After export to the cytoplasm, the pre-miRNA is processed by Dicer to yield a double stranded-miRNA complex. Following the association with the RNA-induced silencing complex (RISC) and the removal of the complementary strand, a mature miRNA cleaves a target mRNA or represses its translation. Ago: Argonaute; m⁷ G: RNA 7-methylguanosine cap.