Gene regulation of connective tissue growth factor: new targets for antifibrotic therapy?

Abstract

Connective tissue growth factor (CTGF) has recently received much attention as a possible key determinant of progressive fibrosis and excessive scarring and also of wound repair, neoangiogenesis, bone formation and embryonic development. CTGF is also up regulated in numerous fibrotic diseases, including atherosclerosis and lung-, skin-, pancreas-, liver- and kidney-fibrosis. TGFβ induces CTGF through different signaling pathways and a specific TGFβ responsive element in the CTGF promoter. CTGF is thought to act both as a profibrotic marker and as a downstream effector of TGFβ by mediating at least some of its profibrotic activities. CTGF is an interesting target for future antifibrotic therapies as it is conceivable that inhibition of CTGF might block the profibrotic effects of TGFβ, without affecting TGFβ's anti-proliferative and immunosuppressive effects. In addition to TGFβ, a number of other regulators of CTGF expression have been identified, including vascular endothelial growth factor, tumor necrosis factor α, shear stress, cell stretch and static pressure, H₂O₂, O₂ and NO. In addition to trans-regulatory mechanisms, specific transcription factor binding sites in the CTGF promoter, as well as 3′untranslated region (UTR) regulatory sequences have been identified that are important for basal and induced CTGF expression. Outlining the mechanisms that underlie CTGF gene regulation in normal and fibrotic cells, might help design of future intervention strategies aiming at targeted specific interference with CTGF expression at sites of progressive fibrosis. In addition, alternative therapies targeting CTGF effects are proposed which might lead to a favorable outcome of wound repair and fibrosis.

Introduction

In tissue response to injury, a proper balance between synthesis and degradation of extracellular matrix (ECM) molecules is of utmost importance for the outcome of the repair process. After initial injury, cytokines are generated which are important in functional restoration (wound repair) of damaged tissue. However, prolonged production of these cytokines can lead to excessive matrix accumulation and chronic fibrosis, often resulting in organ failure and death. One of the cytokines of major importance in this process is TGFβ. In addition to acting as a profibrotic cytokine, TGFβ is a growth factor involved in multiple physiological processes. For example, TGFβ is involved in immunosuppression, and, as it is anti-proliferative for epithelial cells, tumor suppression. Thus, broadly suppressing TGFβ action, for example by use of an anti-TGFβ antibody, might be expected to have deleterious consequences for the patient, especially if such a treatment is used for chronic disorders such as fibrosis. Confirming this notion, homozygous TGFβ1 knockout mice (Bottinger et al., 1997) die shortly after birth due to hyper inflammation. Therefore, more specific targets for antifibrotic therapy are needed that leave TGFβ's positive effects unhindered, while blocking its profibrotic effects.