Connective tissue growth factor: Role in trabecular meshwork remodeling and intraocular pressure lowering

Abstract

Connective tissue growth factor (CTGF) is a distinct signaling molecule modulating many physiological and pathophysiological processes. This protein is upregulated in numerous fibrotic diseases that involve extracellular matrix (ECM) remodeling. It mediates the downstream effects of transforming growth factor beta (TGF-β) and is regulated via TGF-β SMAD-dependent and SMAD-independent signaling routes. Targeting CTGF instead of its upstream regulator TGF-β avoids the consequences of interfering with the pleotropic effects of TGF-β. Both CTGF and its upstream mediator, TGF-β, have been linked with the pathophysiology of glaucomatous optic neuropathy due to their involvement in the regulation of ECM homeostasis. The excessive expression of these growth factors is associated with glaucoma pathogenesis via elevation of the intraocular pressure (IOP), the most important risk factor for glaucoma. The raised in the IOP is due to dysregulation of ECM turnover resulting in excessive ECM deposition at the site of aqueous humor outflow. It is therefore believed that CTGF could be a potential therapeutic target in glaucoma therapy. This review highlights the CTGF biology and structure, its regulation and signaling, its association with the pathophysiology of glaucoma, and its potential role as a therapeutic target in glaucoma management.

Keywords: Antiglaucoma; CTGF; TGF-β; extracellular matrix; fibrosis; remodeling.

Figure 1.

(A) TGF-β signaling via SMAD-dependent and SMAD-independent pathways to regulate CTGF-mediated ECM production. TGF-β signaling is initiated by binding of the ligand with the receptors. In SMAD pathway, the activated receptors phosphorylate SMAD 2 and SMAD 3 together with SMAD 4 to promote CTGF expression. SMAD 7 acts as inhibitory mediator for further stimulation of SMAD signaling. In SMAD-independent pathway, TGF-β activates MAP3K at scaffold protein, JNK-interacting protein-1, which facilitates the activation of MAP2K and JNK MAPK. JNK can also be activated by TAK1 upon polyubiquitylation with TRAF6 at the ligand-bound TGF-βR. Binding of the TGF-βR causing autophosphorylation of tyrosine residues recruits Shc and Grb2. The Shc-Grb2 complex binds to SOS that activates Rac1 and Ras GTPases. Rac1 activates Raf to phosphorylate MKK3/6 and stimulate p38. Ras activates Raf to phosphorylate MEK1 which stimulates ERK1/2. TGF-βR also activates ROCK signaling leading to phosphorylation of JNK and p38. The activation of these MAPK signaling molecules JNK, p38, and ERK1/2 induces the expression of CTGF for ECM synthesis. YAP/TAZ involves binding with the SMAD 2/3/4 complex and directly translocates into the nucleus. The siRNA inhibits the transcription of CTGF gene. The transcription of CTGF gene promotes the CTGF protein synthesis and secretes extracellularly. TGF-β: transforming growth factor β; TGF-βR: TGF-c receptor; SMAD: suppressor of mothers against decapentaplegic; MAP: mitogen-activated protein; MAPK: mitogen-activated protein kinase; JNK: c-Jun amino terminal kinase; TRAF6: tumor necrosis factor: TNF receptor–associated factor 6; TAK1: TGF-β-associated kinase 1; Shc: Src homology domain 2–containing protein; Grb2: growth factor receptor–binding protein 2; SOS: son of sevenless; GTP: guanosine triphosphate; MKK3/6: MAP kinase kinase 3/6; ERK: extracellular signal–regulated kinases; MEK1: MAP/ERK kinase 1; ROCK: RhoA/Rho-associated protein kinase; YAP/TAZ: yes-associated protein 1/transcriptional co-activator with PDZ-binding motif; siRNA: short-interfering RNA; CTGF: connective tissue growth factor. (B) Schematic representation of CTGF protein structure showing four structurally distinct domains and the proteins or growth factors that interact with specific domain. IGFBP: insulin-like growth factor–binding protein; vWC: von Willebrand factor type C; TSP: thrombospondin-1; CT: C-terminal cystine knot; IGF: insulin-like growth factor; TGF-β: transforming growth factor-β; BMP: bone morphogenetic protein; VEGF: vascular endothelial growth factor; LRP: lipoprotein receptor–related protein; HSPGs: heparan sulfate proteoglycans; EGF: epidermal growth factor; ET1: endothelin 1; LPA: lysophosphatidic acid; FN: fibronectin. Created with BioRender.com. Pointed black arrows refer to stimulatory and red blunt arrows refer to inhibitory.

Figure 2.

Factors involved in the regulation of CTGF. TGF-β: transforming growth factor-β; BMP: bone morphogenetic protein; VEGF: vascular endothelial growth factor; IGF-1: insulin-like growth factor 1; ET1: endothelin 1; HSPGs: heparan sulfate proteoglycans; LRP: lipoprotein receptor–related protein; EGF: epidermal growth factor; PDGF: platelet-derived growth factor; sFRP-2: secreted frizzled-like protein-2; FGF-2: fibroblast growth factor 2; LPA: lysophosphatidic acid; AGE: advanced glycation end-products; TNF-α: tumor necrosis factor α; YAP/TAZ: yes-associated protein 1/transcriptional co-activator with PDZ-binding motif. Pointed black arrows refer to stimulatory and red blunt arrows refer to inhibitory. Created with BioRender.com.