The cytokine transforming growth factor-beta (TGF-beta) is a key mediator of fibrosis in all organs. Expression of fibrotic markers in repairing cutaneous wounds is reduced in mice lacking Smad3, a downstream cytoplasmic mediator of TGF-beta signaling (Ashcroft et al., 1999, Nat Cell Biol 1(5):260-266). This is correlated with a reduction in inflammation, and thus in the blood elements thought to be a significant source of TGF-beta at the wound site, the principle form being TGF-beta1. Since the major cellular source of TGF-beta in corneal wounds is the epithelium, and the principal isoform is TGF-beta2, we investigated whether Smad3 deficiency has similar anti-fibrotic effects on corneal repair. In contrast to the situation of cutaneous repair, expression of the fibrotic marker, fibronectin, was equivalent in corneal repair tissue of Smad3-/- mice as compared to their +/- littermates, even though expression of a second fibrotic marker not previously examined in cutaneous wounds, alpha-smooth muscle (sm) actin, was reduced. Also unlike in cutaneous wounds, the inflammatory response was unaffected. These differences between corneal and cutaneous repair correlated with the lack of apparent change in the levels of corneal TGF-beta2. There was a significant reduction of alpha-sm actin expression in stromal cell cultures established from Smad3-/- mice as compared to their +/- littermates, but the rate of cell proliferation stimulated by TGF-beta, as well as expression of fibronectin, was unaffected. Therefore, a deficiency in Smad3 has different effects on corneal and cutaneous repair, probably due to the difference in cellular source and principal isoform of the TGF-beta involved.
2004 Wiley-Liss, Inc.