To MMP or not to MMP: a role for matrix metalloproteinase 3 in primary sclerosing cholangitis?

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease of unknown aetiology, characterized by chronic inflammation and progressive fibrosis of the intraand the extrahepatic bile ducts. The ultimate consequence of this pathology is cholestatic cirrhosis, which manifests approximately 12–17 years following diagnosis (1). The characteristic histopathological lesion in PSC is that of obliterative, non-suppurative bile duct inflammation with periductular fibrosis. The latter changes are often referred to as ‘onion-skin fibrosis’ with reference to the presence of concentric layers of fibrous tissue encircling the bile ducts (2). Comparable morphological features at the level of the intrahepatic bile ducts are exhibited by the most extensively characterized mouse model for PSC, the multidrug resistance gene 2 knock-out (Mdr2 / , also called Abcb4 / ). Bile duct injury through phosphatidylcholine deficiency in bile of these mice leads to periductular fibrosis via massive dysregulation of proand antifibrotic genes (3). What initiates and maintains the fibrotic process in human PSC is not known, and studies to further our insight on genetic determinants and biological pathways involved in the fibrosing components of the pathogenesis are thus of great interest. Homeostasis of extracellular matrix (ECM) is dependent upon a finely tuned balance between synthesis and breakdown. A wide molecular repertoire is involved in the precise regulation of ECM and its components, and the so-called matrix metalloproteinases (MMPs), a family of proteolytic enzymes, is strongly involved in avoiding excess deposition of collagens in the extracellular space (4). In this issue of Liver International, Juran et al. (5) reports on an assessment of the influence of genetic variation in MMP3 on risk of PSC development as well as disease progression. Of particular interest in PSC, MMPs also play key roles in the regulation of inflammation, and typically MMPs are not expressed in non-activated healthy tissue, but rather detected in diseased or inflamed tissue actively repairing and remodelling. The same holds for MMP knock-out mice, which develop severe phenotypes only when challenged by external stress (6). Matrix metalloproteinase 3 is part of a cluster of MMP genes, which localizes to chromosome 11q22.3. The MMP3 gene codes for an enzyme, which is believed to play a pivotal role in ECM degradation and antifibrotic activity because of its broad ECM substrate specificity and its ability to activate other MMPs (Fig. 1). MMP3 is expressed in a wide range of tissues, including bile ducts, liver and gastro-intestinal tract. MMP3 is observed to be expressed transiently upon activation of hepatic stellate cells (HSCs) in response to liver injury, in which HSCs differentiate into a fibroblast-like phenotype (7). An increased expression of MMP3 has also been detected in the inflamed mucosa in inflammatory bowel disease (IBD) (8), which is interesting because 50–80% of PSC patients are concomitantly affected by IBD and shared pathogenetic mechanisms of IBD and PSC are believed to exist (1). MMP3 variants have also been associated with altered susceptibility or severity of other diseases associated with PSC, e.g. celiac disease and colorectal cancer (1, 9, 10). On this general background, the study of MMP3 as a candidate gene in PSC by Juran and colleagues is of great interest. In the study by Juran and colleagues, adequate genetic coverage of MMP3 was accomplished by genotyping eight single nucleotide polymorphisms (SNPs) along with the widely studied promoter 5A6A insertion/deletion polymorphism (rs3025058) in 266 US PSC patients and 407 healthy controls. No association between PSC susceptibility and the individual polymorphisms or inferred haplotypes of the polymorphisms was identified. This was also the case when correcting for overalland subtype-IBD status within the PSC group. However, when considering time to liver transplantation and death within the PSC population, homozygosity for minor alleles of the SNPs rs522616, rs650108 and rs683878 (the last two SNPs were redundant because of strong linkage disequilibrium; r = 0.97) was significantly associated with disease progression [rs522616 hazard ratio (HR) = 2.50, P = 0.032; rs650108, HR = 2.36, P = 0.022]. The significance levels were even more notable among PSC patients with concurrent ulcerative colitis (UC) (rs522616, HR = 3.23, P = 0.013; rs650108, HR = 3.26, P = 0.004). Two previous studies have investigated the role of MMP3 variation in PSC (11, 12). While the study by Juran and colleagues comprehensively assessed genetic variation at the entire MMP3 locus, both these previous studies focused on a single-base insertion/deletion at the promoter position 1171 of MMP3 (relative to the site of initiation of transcription), which has two allelic variants; a sequence of five adenosines (5A allele) and six adenosines (6A allele) respectively. One reason for focusing on the 5A6A polymorphism was the reported influence from this variant on MMP3 expression (13). In