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Purpose: TGFbeta can induce development in lenses of opaque subcapsular fibrotic plaques that have many features of human subcapsular cataracts. To understand further the events associated with the onset and progression of TGFbeta-induced cataract, several different models for anterior subcapsular cataract (ASC) were used and characterized., Methods: Anterior subcapsular plaques were induced in rat lenses cultured with TGFbeta and in transgenic mice overexpressing TGFbeta in the lens. ASC was also examined in lenses of mice haploinsufficient for Pax6, as well as in human biopsy specimens. Immunofluorescence and in situ hybridization labeling were used to examine changes in patterns of gene expression associated with cataract formation in these models., Results: Examination of TGFbeta-induced cataract in transgenic mice established that the subcapsular plaques are composed of a heterogenous cell population: a population of myofibroblastic cells as well as a population of lens-fiber-like cells. Further support for phenotypic change comes from the observation that the cells in these plaques no longer expressed lens epithelial markers, such as Pax6 and Connexin43. Subsequent examination of human biopsy specimens of ASC, as well as lenses from Pax6-deficient mice, showed that the anterior subcapsular plaques in both cases were also composed of a heterogenous population of cells. In contrast, anterior subcapsular plaques that developed in vitro in response to TGFbeta did not have this same cellular heterogeneity, as no fiber-like cells were present., Conclusions: These findings suggest that in vivo, during TGFbeta-induced cataract formation, some lens epithelial cells transform into myofibroblastic cells, whereas others differentiate into fiber cells. As this pathologic change is accompanied by altered expression of genes characteristic of the normal lens epithelial cell phenotype and as lenses from Pax6-deficient mice exhibit development of anterior subcapsular plaques closely resembling those induced by TGFbeta in transgenic mice, the authors propose that a reduction in Pax6 levels may be essential for this pathologic process to progress. Furthermore, it is clear from these in vitro studies that TGFbeta alone cannot reproduce the same morphologic and molecular changes associated with ASC formation in vivo, indicating that additional molecule(s) in the eye are important in this process.

Transforming growth factor-beta2 (TGF-beta2) induces anterior subcapsular cataracts, with a marked increase in cytoskeletal and extracellular matrix proteins, such as alpha-smooth muscle actin (alphaSMA). It has been shown that 17beta-estradiol (E2) can prevent TGF-beta2-induced cataracts in lenses from ovariectomized female rats. The purpose of the current study was to extend this finding by testing whether E2 can prevent TGF-beta2-induced cataracts and inhibit the induction of alphaSMA gene expression in normal male and normal, non-ovariectomized female rats.Sex-specific differences were observed in 17-week-old rat lenses incubated in 0.15 ng ml(-1) TGF-beta2 and in 10(-8)M E2 plus TGF-beta2. TGF-beta2 induced approximately twice as many anterior subcapsular plaques and 1.5 times the level of alphaSMA transcripts in male lenses compared to female lenses. Notably, E2 inhibited plaque formation and the induction of alphaSMA transcripts in female rat lenses but not in male rat lenses. E2 also inhibited the induction of alphaSMA in TGF-beta2-incubated lenses from ovariectomized female rats.E2 prevented lens opacification and the induction of alphaSMA gene expression in female, but not male, lenses. This sex-specific difference may have implications for studies on the therapeutic use of estradiol for treatment of secondary cataract.

Purpose: In a previous study, it was determined that TGFbeta induces cataractous changes in the rat lens in vitro. The purpose of the present study was to determine whether the introduction of biologically active TGFbeta into the vitreous stimulates cataractous changes in the rat lens in situ., Methods: TGFbeta was injected into the vitreous of the left eye of anesthetized adult male Wistar rats. The right eye received sterile vehicle as a control. Three to four months after injection, animals were killed, and lenses were enucleated and examined for cataractous changes., Results: All lenses from control eyes remained transparent and maintained normal cellular architecture throughout. In contrast, lenses from TGFbeta-injected eyes displayed cloudiness in the cortex. In some lenses, distinct opacities were also apparent at the equator and extending some distance toward the anterior and posterior poles. Histologically, the opacities corresponded to subcapsular plaques containing aberrant cells and accumulations of extracellular matrix. In addition, cortical fibers in the anterior and posterior of all lenses displayed variable degrees of swelling, and many retained their nuclei. In some regions, the fiber cells appeared to have degenerated to form large homogeneous areas. The cellular architecture of the equator of these lenses was also disrupted and, in the most severe case, no bow zone was apparent with nucleated cells extending to the posterior pole., Conclusion: The introduction of active TGFbeta into the vitreous induced lenses to undergo cataractous changes. In addition to the TGFbeta-induced changes in the epithelium that were reported previously, cataractous changes observed in this study also involved the lens fiber cells and resembled changes observed in human posterior subcapsular and cortical cataracts.

Cataract, already a major cause of visual impairment and blindness, is likely to become an increasing problem as the world population ages. In a previous study, we showed that transforming growth factor-beta (TGFP) induces rat lenses in culture to develop opacities and other changes that have many features of human subcapsular cataracts. Here we show that estrogen protects against cataract. Lenses from female rats are more resistant to TGFbeta-induced cataract than those from males. Furthermore, lenses from ovariectomized females show increased sensitivity to the damaging effects of TGFbeta and estrogen replacement in vivo, or exposure to estrogen in vitro, restores resistance. Sex-dependent and estrogen-related differences in susceptibility to cataract formation, consistent with a protective role for estrogen, have been noted in some epidemiological studies. The present study in the rat indicates that estrogen provides protection against cataract by countering the damaging effects of TGFbeP. It also adds to an increasing body of evidence that hormone replacement therapy protects postmenopausal women against various diseases.