Hope for disease-modifying treatment of systemic sclerosis/scleroderma.

Systemic sclerosis (SSc) is a connective tissue disease of inner organs and skin. Its cutaneous manifestations are called scleroderma but the terms “systemic sclerosis” and “scleroderma” are sometimes used interchangeably (Fett, 2013). The American College of Rheumatology and the European League against Rheumatism have recently issued a consensus statement for the classification of SSc (van den Hoogen et al., 2013), but the classification of this condition has not been universally accepted (Nihtyanova et al., 2014). SSc has a prevalence of up to 1 in 1000 people, apparently depending on ethnicity, and it predominantly affects women, mostly in the third to fifth decade of their lives (D’Amico et al., 2013). It is a debilitating and often fatal condition for which no approved disease-modifying treatment exists (Ho et al., 2014; Nihtyanova et al., 2014). Therefore, a recent article in the Journal of Pharmacology and Experimental Therapeutics (Haak et al., 2014) is a sign of hope; the clinically available symptomatic and palliative treatments have been reviewed elsewhere (Bournia et al., 2009). SSc is characterized by progressive fibrosis not only of the skin but also of multiple inner organs, including the lungs, heart, kidney, and gastrointestinal tract (Ho et al., 2014). Although fibrosis of the skin causes sometimes severe functional impairment, it is the fibrosis of the inner organs that ultimately leads to fatal outcomes. The pathogenesis of SSc remains to be defined in detail, but it involves chronic tissue injury, endoplasmic reticulum stress, endothelial dysfunction, pericyte activation, and aberrant T cell–driven autoimmunity. Eventually, the final common pathway is the activation of fibroblasts, their transition to myofibroblasts, and excessive extracellular matrix deposition (Denton et al., 2006; Wynn and Ramalingam, 2012). The recent work of Haak et al. (2014) is based on the concept that gene transcription induced by serum response factor is a critical driver of myofibroblast activation by nearly all factors leading to fibrosis. Such serum response factor–regulated gene expression involves Rho-GTPase–stimulated nuclear localization of its transcription coactivator myocardin-related transcription factor (MRTF). In support of this concept, Haak et al. (2014) demonstrate spontaneous activation of anMRTF-regulated gene transcription program in dermal fibroblasts from SSc patients. More importantly, they have identified a small molecule, CCG203971 [N-(4-chlorophenyl)-1-{[3-{furan-2-yl)phenyl]carbonyl}piperidine-3-carboxamide], an improved analog of CCG-1423 [2-({[3,5-bis(trifluoromethyl)phenyl]formamido}oxy)-N-(4-chlorophenyl)propanamide] (Fig. 1), that blocks MRTF nuclear localization by interfering with the microtubule-associated mono-oxygenase, calponin and LIM domain–containing 2 (MICAL-2)–mediated regulation of intranuclear actin polymerization. In in vitro studies, CCG-203971 inhibited the enhanced proliferation of SSc-derived dermal fibroblasts but not that of normal fibroblasts. It also reversed the myofibroblast phenotype of transforming growth factor-b–stimulated normal dermal fibroblasts and the spontaneous activation of SSc-derived fibroblasts with a potency of about 3 mM; in this assay, CCG203971 was about 100-fold more potent than pirfenidone (Fig. 1; Schaefer et al., 2011), a drug currently in phase II studies for the treatment of SSc patients. Furthermore, CCG-203971 prevented the development of bleomycin-induced skin thickening and collagen deposition in mice in vivo. It is a long journey fromnonclinical findings like those of Haak et al. (2014) to a safe and effective treatment of SSc and other fibrotic conditions. Given the plethora of chemokines, hormones, and growth and paracrine factors implied in fibrosis development (Denton et al., 2006; Wynn and Ramalingam, 2012), it is This Commentary is in reference to “Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury,” found in J Pharmacol Exp Ther 2014, 349:480–486. dx.doi.org/10.1124/jpet.114.213520comm.