TGFβ pathobiology in the eye

Transforming growth factor beta (TGF beta), a multifunctional growth factor, is one of the most important ligands involved in the regulation of cell behavior in ocular tissues in physiological or pathological processes of development or tissue repair, although various other growth factors are also involved. Increased activity of this ligand may induce unfavorable inflammatory responses and tissue fibrosis. In mammals, three isoforms of TGFb, that is, beta 1, beta 2, and beta 3, are known. Although all three TGFb isoforms and their receptors are present in ocular tissues, lack of TGF beta 2, but not TGF beta 1 or TGF beta 3, perturbs embryonic morphogenesis of the eyes in mice. Smads2/3 are key signaling molecules downstream of cell surface receptors for TGFb or activin. Upon TGF binding to the respective TGF receptor, Smads2/3 are phosphorylated by the receptor kinase at the C-terminus, form a complex with Smad4 and translocate to the nucleus for activation of TGF beta gene targets. Moreover, mitogen-activated protein kinase, c-Jun N-terminal kinase, and p38 modulate Smad signals directly via Smad linker phosphorylation or indirectly via pathway crosstalk. Smad signals may therefore be a critical threrapeutic target in the treatment of ocular disorders related to fibrosis as in other systemic fibrotic diseases. The present paper reviews recent progress concerning the roles of TGF beta signaling in the pathology of the eye.