Sticking it to Scleroderma: Potential Therapies Blocking Elevated Adhesive and Contractile Signaling

Abstract

During repair of connective tissue, resting fibroblasts become 'activated'; that is, they migrate into the wound where they synthesize and remodel new extracellular matrix. The differentiated fibroblast responsible for this action is termed the myofibroblast, which expresses the highly contractile protein smooth muscle actin ( SMA) and is responsible for the synthesis and remodeling of extracellular matrix (ECM). Persistence of the myofibroblast is a key characteristic of fibrotic diseases including scleroderma. Proteins such as transforming growth factor (TGF ), endothelin-1 (ET-1), connective tissue growth factor (CCN2/CTGF) and platelet derived growth factor (PDGF) are believed to contribute to myofibroblast differentiation and persistence. Moreover, it is now known that elevated adhesive and contractile signaling is a key feature of fibrotic fibroblasts. This review summarizes recent findings aimed at developing new, rationallydesigned therapies for the fibrosis in scleroderma.

PAI‐1 in tissue fibrosis

“…In recent years, enormous progress has been made in our understanding of the molecular bases of tissue fibrosis. Along with a series of in vitro experiments using cultured cells from different organs, various animal models (induced/injured and spontaneous/uninjured) of tissue fibrosis have been used to explore the molecular basis of fibrosis in vivo (Ellmers, 2010; Leask, 2010; Mastuzaki, 2010; Yang et al, 2010; Yue et al, 2010). The widely used animal models of tissue fibrosis include the following: For skin and lung fibrosis, the bleomycin-induced mouse model (Murray et al, 2008; Wu et al, 2004a,2009; Yamamoto et al, 1999) and the graft-versus-host disease (GVHD) mouse model (McCormick et al, 1999); for cardiac fibrosis, the transverse aortic banding (TAB) model (Sun et al, 2007), angiotensin II (AngII)–induced model (Lijnen et al, 2000), phenylephrine-induced model (Farivar et al, 1995), isoproterenol-induced model (Rohrer et al, 1996), and aldosterone-induced model (Lijnen and Petrov, 2000); for kidney fibrosis, the unilateral ureteral obstruction (UUO)–induced model and aldosterone-induced renal injury model (Ma et al, 2006; Ma and Fogo, 2009; Oda et al, 2001); for liver fibrosis, the carbon tetrachloride (CCl 4 )–induced mouse model and bile duct ligation model (Wang et al, 2007); and for gastrointestinal tract fibrosis, the chronic 2,4,6-trinitrobenzene sulfonic acid–induced colitis model (Wu and Chakravarti, 2007).…”

“…Fibrosis is a very common end-stage pathologic manifestation of several diseases including systemic sclerosis, pulmonary hypertension, renal hypertension, cardiac hypertension, myocardial infarction (MI), alcoholic liver disease and nonalcoholic steatohepatitis (NASH) (Berk et al, 2007; Brunt, 2004; Ellmers, 2010; Ghosh, 2010; Jansen et al, 2004; Leask, 2010; Mastuzaki, 2010; Pohlers et al, 2009; Varga and Abraham, 2007; Vaughan et al, 2007; Wynn, 2008; Yang et al, 2010; Yue et al, 2010). Although the etiology of fibrosis in different organs is not properly defined, numerous studies suggest that at the molecular level, fibrogenic processes in different organs may share common mechanisms (Ghosh, 2010; Wynn, 2007, 2008).…”

Molecular basis of organ fibrosis: Potential therapeutic approaches

“…5 There is no effective therapy for the treatment of fibrosis, an end stage pathological manifestation (a difficult-to-treat disease state) of a wide variety of diseases including systemic sclerosis (SSc), myocardial infarction (MI), glomerulosclerosis, tubulointerstitial fibrosis, myocardial infarction, chronic hypertension, idiopathic pulmonary fibrosis (IPF), and liver cirrhosis. 2,[6][7][8][9][10][11] In order to understand the basis of fibrogenesis, numerous in vitro and in vivo cellular and molecular studies have been undertaken in the last two decades. Using in vitro cell cultures (unstimulated controls, cytokine-induced in vitro model of fibrotic cells as well as cells isolated from fibrotic tissues), investigators dissected out the profibrotic and antifibrotic signaling pathways.…”

Fibrosis: is it a coactivator disease?

“…Abnormality in ECM protein synthesis and or proteolytic activities disrupts tissue homeostasis and leads to an abnormal matrix remodeling, the salient feature fibrosis, in different organs (1)(2)(3)(4)(5)(6)(7)(8)(9). Fibrosis is associated with numerous diseases including hypertension-induced-cardiac hypertrophy, myocardial infarction, heart failure, liver failure, renal failure, lung diseases, systemic sclerosis, and atherosclerosis (10)(11)(12)(13)(14)(15)(16)(17). Fibrosis is characterized by initial vascular injury, mononuclear cell infiltration, secretion of cytokines, migration, proliferation and activation of fibroblasts, epithelial-to-mesenchymal transition (EMT)/endothelial-tomesenchymal transition (EndMT), myofibroblast differentiation, synthesis of excessive non-physiological levels of collagen and other extracellular matrix proteins.…”

“…The pleiotropic cytokine, TGF-β plays a pivotal role in the processes of inflammation and fibrogenesis. TGF-βactivated resident fibroblasts or EMT/EndMT-derived fibroblast-like cells differentiate to myofibroblasts which produce elevated levels of collagen, the major extracellular matrix proteins in fibrotic tissues (3,5,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”