Background Scleroderma is a chronic connective tissue disease of unknown aetiology. In early stages, vascular injury and inflammation lead to fibrosis, resulting in irreversible damage in various organs. Inflammation is believed to be necessary in order to activate fibroblasts to over-produce extracellular matrix components. At the present, there is no effective standard treatment to reverse or slow down the progression of scleroderma but one of the feasible approaches is to target key inflammatory pathways that are involved in the pathogenesis of the disease.
MKP-1 (Mitogen-Activated Protein Kinase Phosphatase-1) is a nuclear phosphatase present in most cell types and tissues. Studies with MKP-1 deficient mice have undoubtedly shown that MKP-1 is an important regulator of innate and adaptive immune responses to limit and suppress inflammation (1) but its role in fibrosing diseases has not been studied.
Objectives In the present study, we aimed to investigate the potential protective role of MKP-1 in the pathogenesis of scleroderma by using MKP-1 deficient mice and a widely studied experimental model of scleroderma.
Methods We used bleomycin-induced dermal fibrosis in the mouse as an experimental model of scleroderma (2). Wild type (WT) and MKP-1 deficient mice were injected subcutaneously with bleomycin every other day for 28 days. Dermal thickness and collagen accumulation were determined by histological analyses. The expression of several inflammatory and pro-fibrotic mediators were measured by quantitative RT-PCR.
Results We found that bleomycin-induced dermal thickness and lipodystrophy were increased in MKP-1 deficient mice. Collagen accumulation in the dermis and mRNA expression of collagens 1A1 and 3A1 were enhanced in the skin from MKP-1 deficient mice as compared to the skin from WT animals. Affected skin from MKP-1 deficient mice presented increased expression of factors related to inflammation and fibrosis, namely IL-6, TGF-β1, fibronectin-1 and YKL-40 as well as chemokines MCP-1, MIP-1α and MIP-2.
Conclusions This study demonstrates, for the first time, that MKP-1 deficient mice develop more severe bleomycin-induced dermal fibrosis than their WT counterparts, indicating that MKP-1 regulates the inflammatory and fibrotic processes typical for experimentally-induced scleroderma. These findings suggest that compounds which enhance expression/activity of MKP-1 have potential as novel drugs for the stage-specific modulation of the pathogenesis of scleroderma.
Korhonen R, Moilanen E. Mitogen-activated protein kinase phosphatase 1 as an inflammatory factor and drug target. Basic Clin Pharmacol Toxicol. 2014; 114:24–36.
Yamamoto T et al. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol. 1999; 112:456–62.
Disclosure of Interest None declared