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

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.