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Review
. 2010 Aug;10(6):565-78.
doi: 10.2174/1566524011009060565.

Role of transforming growth factor Beta in corneal function, biology and pathology

A Tandon  1 , J C K Tovey, A Sharma, R Gupta, R R Mohan
Affiliations
Review

Role of transforming growth factor Beta in corneal function, biology and pathology

A Tandon et al. Curr Mol Med. 2010 Aug.

Abstract

Transforming growth factor-beta (TGFbeta) is a pleiotropic multifunctional cytokine that regulates several essential cellular processes in many parts of the body including the cornea. Three isoforms of TGFbeta are known in mammals and the human cornea expresses all of them. TGFbeta1 has been shown to play a central role in scar formation in adult corneas whereas TGFbeta2 and TGFbeta3 have been implicated to play a critical role in corneal development and scarless wound healing during embryogenesis. The biological effects of TGFbeta in the cornea have been shown to follow Smad dependent as well as Smad-independent signaling pathways depending upon cellular responses and microenvironment. Corneal TGFbeta expression is necessary for maintaining corneal integrity and corneal wound healing. On the other hand, TGFbeta is perhaps the most important cytokine in the pathogenesis of fibrotic disease in the cornea. Although the transformation of keratocytes to myofibroblasts induced by TGFbeta is largely believed to cause corneal fibrosis or scarring, the precise molecular mechanism(s) involved in this process is still unknown. Currently no drugs are available to treat corneal scarring effectively without causing significant side effects. Many approaches to treat TGFbeta-mediated corneal scarring are under investigation. These include blocking of TGFbeta, TGFbeta receptor, TGFbeta function and/or TGFbeta maturation. Other strategies such as modulating keratocyte proliferation, apoptosis, transcription and DNA condensation are also being investigated. The potential of gene therapy to neutralize the pathologic effects of TGFbeta has also been demonstrated recently.

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Figures

Fig. (1)
Fig. (1)
Schematic representation of the protein structure related to TGFβ. An N-terminal hydrophobic signal peptide region (30 amino acids), the latent associated peptide (LAP) (249 amino acids) region and the C-terminal, a mature bioactive TGFβ region.
Fig. (2)
Fig. (2)
Schematic representation of TGFβ maturation. Precursor pro-TGFβ is cleaved by endopeptidase in Golgi apparatus to form small latent complex. This complex then covalently binds with latent TGFβ binding protein (LTBP) and forms the large latent complex that is finally released into the ECM as mature TGFβ.
Fig. (3)
Fig. (3)
TGFβ Smad-dependent signaling pathway: TGFβ exerts its effect by binding and activating type II receptor (TGFβR2) and then type I receptor (TGFβR1). After phosphorylation, TGFβR2 phosphorylates TGFβR1, which subsequently phosphorylates and activates R-Smads (Smad2/3). Activated R-Smads are released from receptors then form a heterotrimeric complex with co-Smad (Smad4), which is translocated into the nucleus to regulate transcription of the target gene. I-Smads (Smad6 and Smad7) shows inhibitory Smad interaction and interfere with the activation of R-Smads while Smurf1/2 targets TGFβR-1 and TGFβR-2 along with various Smad family proteins for proteasome-mediated degradation.
Fig. (4)
Fig. (4)
Schematic diagram of R-Smad containing MH-1 and MH-2 regions at amino (N) and carboxyl (C) terminal respectively linked together by variable linker region and specific phosphorylation motif, SSxS, at C-terminus.
Fig. (5)
Fig. (5)
TGFβ Smad-independent Signaling Pathways: TGFβ exerts its effect by binding and activating type II receptor (TGFβR2) and then type I receptor (TGFβR1). Smad independent pathways are then activated and include various branches of MAP kinase (MAPK) pathways, Rho-like GTPase signaling pathways, phosphatidylinositol-3-kinase (PI3K)/AKT pathways and protein phosphatase 2A (PP2A) pathway. These pathways then regulate gene transcription in the nucleus. The exact mechanism of activation of these various Smad-independent signaling pathways remains to be elaborated.
Fig. (6)
Fig. (6)
Representative immunofluorescence images showing time-dependent expression and localization of TGFβ1 in −9.0 D PRK-treated rabbit cornea. PRK caused a significant increase in TGFβ1 in the stroma at day 1 and day 3 (p<0.001 or <0.01) compared to naïve corneas. The elevated level of TGFβ1 showed progressive decline as extremely low or no expression was detected at day 7 or day 14 in the stroma. The naïve corneas did not show any TGFβ1 expression (data not shown). Scale bar denotes 50 µm.
Fig. (7)
Fig. (7)
Representative immunofluorescence images showing time-dependent expression and localization of TGFβ2 in −9.0 D PRK-treated rabbit cornea. PRK induced TGFβ2 expression in the stroma at an early time points (day 1 and day 3) as no expression of TGFβ2 was detected in naïve corneas (data not shown). Scale bar denotes 50 µm.
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