Contribution of activin receptor–like kinase 5 (transforming growth factor β receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts

Abstract

Objective. To use a specific transforming growth factor ␤ receptor type I (TGF␤RI; activin receptor-like kinase 5 [ALK-5]) kinase inhibitor (SD208) to determine the role of activation of the TGF␤RI kinase (ALK-5) in maintaining the profibrotic phenotype of dermal fibroblasts in systemic sclerosis (SSc).Methods. The effect of SD208 on the expression of key biochemical markers of the fibrotic phenotype was compared in fibroblasts cultured from clinically involved (lesional) and clinically uninvolved skin of patients with diffuse cutaneous SSc (dcSSc) and in fibroblasts from healthy controls matched for age, sex, and anatomic site. Protein expression was compared together with the ability of fibroblasts to adhere to the extracellular matrix and to remodel and contract a free-floating fibroblast-populated type I collagen lattice.Results. Inhibiting TGF␤RI kinase reduced the expression of a cohort of fibrotic markers by dermal fibroblasts from patients with dcSSc, including type I collagen and ␤1 integrin. Moreover, inhibition also attenuated the elevated adhesive and contractile abilities of dcSSc fibroblasts.

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

“…However, the complexity of the profibrotic effects of TGF␤ that involve both Smad3-dependent and -independent mechanisms presents a challenge in selecting appropriate therapeutic targets. For example, pharmacologic inhibitors of TGF␤RI kinase that result in blockade of Smad3 signaling (ALK-5 kinase inhibitors) did normalize elevated CCN2 levels in SSc fibroblasts and, in general, ameliorated only selected aspects of SSc fibrosis in vitro (35,36). Our study suggests that due to the pleiotropic nature of TGF␤ signaling, targeting a single component of the TGF␤ signaling pathway may not be effective in ameliorating SSc fibrosis.…”

FAK Is Required for TGFβ-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix-remodeling Phenotype

“…Prior reports have focused on general TGF␤ signaling pathway, including TGF␤ receptors and Smads, in the production and remodeling of ECM (Verrecchia and Mauviel, 2002;Verrecchia et al, 2006). However, it is now appreciated that selective modulation of profibrotic signaling downstream of TGF␤ would be beneficial in promoting and controlling the wound healing and scarring while leaving other effects of TGF␤ unaltered (Leask et al, 2003;Leask and Abraham, 2004;Chen et al, 2006).…”

“…TGF␤ also induces ECM synthesis and remodeling and myofibroblast differentiation (Leask and Abraham, 2004). Exaggerated TGF␤ signaling in fibroblasts contributes to chronic fibrosis (Chen et al, 2005(Chen et al, , 2006. The intracellular signaling pathway downstream to the TGF␤ receptors is mediated by the Smad family of transcription factors (Shi and Massague, 2003).…”

Adamts5 Deletion Blocks Murine Dermal Repair through CD44-mediated Aggrecan Accumulation and Modulation of Transforming Growth Factor β1 (TGFβ1) Signaling

“…In the context of this study, TGF␤1 stimulates col1 and col3 production by fibroblasts and is required for terminal differentiation of myofibroblasts during wound contracture (27). Furthermore, the pro-fibrotic effects of TGF␤1 on both normal and scleroderma skin-derived fibroblasts require signaling through ALK5 and phosphorylation of Smad2/3 (28,29). We have recently shown that TS5-mediated cleavage of aggrecan is required for the pro-fibrotic responses of synovium, meniscus, and cartilage in murine models of osteoarthritis (30) and also the fibrogenic phase of ligament repair in equine degenerative suspensory ligament desmitis (31).…”