The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome

Werner syndrome (WS) is a genetic disorder where individuals show premature onset of many clinical features of old age and is used as a model to investigate normal ageing processes [1]. The molecular mechanism of WS is related to accelerated cell ageing. Normal human cells divide a limited number of times before entering replicative senescence [2]. This is postulated to contribute to normal human ageing [1] and fibroblasts from WS patients have a much-reduced replicative capacity [3]. The premature senescence of WS cells is thought to be a stress response, and the stress-induced p38 MAP kinase pathway is activated in young WS cells [3]. Treatment with the p38 inhibitor SB203580 increased the growth rate and the cellular life span of primary WS fibroblasts, and rescued their senescent-like morphology [3]. Essentially, SB203580 reverted the phenotypic characteristics of WS fibroblasts, implicating a role for both p38 and stress signalling in WS. These data suggested a possible therapeutic role for p38 inhibitors in WS [4]. However, it has been shown that long-term use of p38 inhibitors in both humans and mice has toxic effects and low therapeutic efficacy [5]. The reasons for this are unknown but may relate to the complexities of the pathways regulated by p38, which is at the hub of the stress-induced response and regulates many downstream kinases and cellular processes [6]. It has thus been suggested that targeting proteins downstream of p38 may be advantageous due to the more limited pathways affected. MAPKAPK2 (MK2) is one particularly attractive target [7] as it is known to regulate the cell cycle [8], is involved in regulating cellular morphology [9], and plays a role in inflammatory processes [10] that are prevalent in WS [4]. In addition, the observation that mice null for MK2 are viable, whereas mice null for p38 are lethal, suggests that therapeutic inhibition of MK2 may prove less problematical than p38 inhibition [10].Previous work using MK2 inhibitors in W