Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPase-regulated gene transcription - PubMed (original) (raw)

Review

Cellular mechanisms of tissue fibrosis. 8. Current and future drug targets in fibrosis: focus on Rho GTPase-regulated gene transcription

Pei-Suen Tsou et al. Am J Physiol Cell Physiol. 2014.

Abstract

Tissue fibrosis occurs with excessive extracellular matrix deposition from myofibroblasts, resulting in tissue scarring and inflammation. It is driven by multiple mediators, such as the G protein-coupled receptor ligands lysophosphatidic acid and endothelin, as well as signaling by transforming growth factor-β, connective tissue growth factor, and integrins. Fibrosis contributes to 45% of deaths in the developed world. As current therapeutic options for tissue fibrosis are limited and organ transplantation is the only effective treatment for end-stage disease, there is an imminent need for efficacious antifibrotic therapies. This review discusses the various molecular pathways involved in fibrosis. It highlights the Rho GTPase signaling pathway and its downstream gene transcription output through myocardin-related transcription factor and serum response factor as a convergence point for targeting this complex set of diseases.

Keywords: Rho GTPase; drug development; fibrosis; gene transcription; therapeutics.

Copyright © 2014 the American Physiological Society.

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Figures

Fig. 1.

Fig. 1.

Rho GTPase signaling pathway represents a convergent approach to targeting fibrosis. Many current drugs being developed for fibrotic diseases are targeting specific receptors known to be involved in stimulating fibroblasts into myofibroblasts. Interestingly, many of these specific receptor systems converge onto Rho small GTPase signaling. GTP-bound active Rho can interact with downstream effector proteins, most notably Rho-associated, coiled-coil containing protein kinase (ROCK) kinase and mouse diaphanous-related formin-1 (mDia1), which together initiate and stabilize actin stress fibers. This increase in F-actin and resulting decrease in G-actin monomers frees myocardin-related transcription factor (MRTF) to translocate into the nucleus where it cooperates with serum response factor (SRF) to induce gene transcription. Many MRTF/SRF target genes are known drivers of fibrosis including connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen; together this activation of gene transcription induces and maintains the activation of fibroblasts to myofibroblasts. GPCR, G protein-coupled receptor; TGFβ, transforming growth factor-β.

Fig. 2.

Fig. 2.

Schematic model of current therapeutic approaches. Several receptor mechanisms being targeted in fibrosis are illustrated. All can activate Rho GTPase and the downstream MRTF/SRF gene transcription mechanism. By blocking MRTF-regulated gene transcription and myofibroblasts, our compounds (e.g., CCG-203971) represent a novel approach targeting a key convergence point (genetic switch) in the intrinsic fibroblast-myofibroblast conversion. This may prove more effective than attempting to disrupt each individual profibrotic input. LPA, lysophosphatidic acid; LARG: Leukemia-associated RhoGEF; GEF: guanine nucleotide exchange factor.

Fig. 3.

Fig. 3.

The fibroblast-to-myofibroblast transition requires MRTF/SRF gene transcription. α-SMA-expressing myofibroblasts are responsible for the excess deposition of extracellular matrix components observed in pathological fibrosis. Most notably, collagen and fibronectin play important roles in the contractile and fibrous tissue. A variety of microenvironment conditions including growth factors, cytokines, mechanical stress and adhesion proteins combine to propagate the stimulatory response into MRTF/SRF-regulated gene transcription and transition into a myofibroblast state.

Fig. 4.

Fig. 4.

CCG-203971 modulates myofibroblast transition of dermal fibroblasts. A: primary human dermal fibroblasts from normal donors were treated with or without 10 ng/ml TGFβ for 3 days to induce a myofibroblast transition; during stimulation, cells were also treated with 10 μM CCG-203971 or DMSO. CCG-203971 markedly decreased α-SMA levels induced by TGFβ. Two representative individual samples are shown. B: elevated α-SMA expression in dermal fibroblasts from patients with diffuse systemic sclerosis (SSc) was blocked by CCG-203971. Two representative individual samples are shown. DAPI, 4′,6-diamidino-2-phenylindole. [From Haak et al. (40). Adapted with permission from the American Society for Pharmacology and Experimental Therapeutics.]

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