Older women develop more cataracts than men of comparable age. It is believed that this is due to the loss of estrogen after menopause. Support for this hypothesis comes from epidemiological studies, which show that hormone replacement therapy reduces the risk of cataract, and from animal studies, which show that estradiol prevents TGF-beta-induced anterior subcapsular cataracts in ovariectomized rats. Our laboratory has been interested in the protective role of estradiol and has used the TGF-beta cataract model to examine the effects of TGF-beta and estradiol in lenses from normal male and female rats. In the presence of low concentrations of TGF-beta2 (0.15 ng/ml), cultured male rat lenses developed twice as many cataract plaques as female rat lenses. Estradiol (10-8M) prevented cataracts in female lenses, but not male lenses. In parallel, the anterior subcapsular cataract marker, alpha-smooth muscle actin, was up regulated in both male and female rat lenses, but down regulated only in female lenses in the presence of estradiol. These findings suggest that there may be sex-specific differences in the level of estrogen receptors. The TGF-beta2 model has many similarities with human anterior subcapsular cataracts and secondary cataracts. Anterior subcapsular cataracts obscure vision, because of their central location in the optical axis. The cataract is the result of an abnormal accumulation of epithelial cells that produce proteins not normally present in the lens, such as, alpha-smooth muscle actin, types I and III collagen, and fibronectin. In secondary cataracts, posterior capsular opacification occurs after cataract surgery as a result of invasion by residual lens epithelial cells. Wrinkling of the capsule and accumulation of extracellular matrix material are hallmarks of this pathology. Secondary cataracts require YAG laser capsulotomy. Therapeutic alternatives that hold promise in retarding lens cell migration include inhibition by thapsigargin, FGF receptor-1, TGF-beta, and integrin antagonists. Estradiol may fall in this category. However, the current study indicates that male-female differences will need to be considered when testing this alternative.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Intramural Research (Z01)
Project #
1Z01EY000312-07
Application #
6826704
Study Section
(LMOD)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2003
Total Cost
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Cox, Constance A; Amaral, Juan; Salloum, Rita et al. (2010) Doxycycline's effect on ocular angiogenesis: an in vivo analysis. Ophthalmology 117:1782-91
Chen, Zhengguang; John, Molykutty; Subramanian, Saradha et al. (2004) 17Beta-estradiol confers a protective effect against transforming growth factor-beta2-induced cataracts in female but not male lenses. Exp Eye Res 78:67-74
Dufour, Eric M; Nandrot, Emeline; Marchant, Dominique et al. (2003) Identification of novel genes and altered signaling pathways in the retinal pigment epithelium during the Royal College of Surgeons rat retinal degeneration. Neurobiol Dis 14:166-80
Darmanin, Connie; Iwata, Takeshi; Carper, Deborah A et al. (2003) Expression, purification and preliminary crystallographic analysis of human sorbitol dehydrogenase. Acta Crystallogr D Biol Crystallogr 59:558-60
Carper, D; John, M; Chen, Z et al. (2001) Gene expression analysis of an H(2)O(2)-resistant lens epithelial cell line. Free Radic Biol Med 31:90-7
Lichtstein, D; McGowan, M H; Russell, P et al. (2000) Digitalis and digitalislike compounds down-regulate gene expression of the intracellular signaling protein 14-3-3 in rat lens. Hypertens Res 23 Suppl:S51-3
Frederikse, P H; Zigler Jr, S J; Farnsworth, P N et al. (2000) Prion protein expression in mammalian lenses. Curr Eye Res 20:137-43
Singh, S B; Malamas, M S; Hohman, T C et al. (2000) Molecular modeling of the aldose reductase-inhibitor complex based on the X-ray crystal structure and studies with single-site-directed mutants. J Med Chem 43:1062-70
Sun, J K; Iwata, T; Zigler Jr, J S et al. (2000) Differential gene expression in male and female rat lenses undergoing cataract induction by transforming growth factor-beta (TGF-beta). Exp Eye Res 70:169-81
Carper, D A; Sun, J K; Iwata, T et al. (1999) Oxidative stress induces differential gene expression in a human lens epithelial cell line. Invest Ophthalmol Vis Sci 40:400-6

Showing the most recent 10 out of 12 publications