Abstract
Posterior capsular opacification (PCO) is the major complication arising after cataract treatment. PCO occurs when the lens epithelial cells remaining following surgery (LCs) undergo a wound healing response producing a mixture of α-smooth muscle actin (α-SMA)-expressing myofibroblasts and lens fibre cells, which impair vision. Prior investigations have proposed that integrins play a central role in PCO and we found that, in a mouse fibre cell removal model of cataract surgery, expression of αV integrin and its interacting β-subunits β1, β5, β6, β8 are up-regulated concomitant with α-SMA in LCs following surgery. To test the hypothesis that αV integrins are functionally important in PCO pathogenesis, we created mice lacking the αV integrin subunit in all lens cells. Adult lenses lacking αV integrins are transparent and show no apparent morphological abnormalities when compared with control lenses. However, following surgical fibre cell removal, the LCs in control eyes increased cell proliferation, and up-regulated the expression of α-SMA, β1-integrin, fibronectin, tenascin-C and transforming growth factor beta (TGF-β)–induced protein within 48 hrs, while LCs lacking αV integrins exhibited much less cell proliferation and little to no up-regulation of any of the fibrotic markers tested. This effect appears to result from the known roles of αV integrins in latent TGF-β activation as αV integrin null lenses do not exhibit detectable SMAD-3 phosphorylation after surgery, while this occurs robustly in control lenses, consistent with the known roles for TGF-β in fibrotic PCO. These data suggest that therapeutics antagonizing αV integrin function could be used to prevent fibrotic PCO following cataract surgery.
Highlights
Cataract is a clouding of the ocular lens, which is the most common cause of blindness in the world [1] with 43% of the 44.8 million blind suffering from cataract [2]
We demonstrate that integrins belonging to the aV family are not essential for lens maturation or homoeostasis, but are up-regulated at the protein level in the lens cells (LCs) remaining on the lens capsule in a mouse model of cataract surgery
It has been previously postulated that aV integrins play a major role in lens epithelial cell epithelial–mesenchymal transition (EMT) [17, 18], little experimental evidence for this idea has been reported
Summary
Cataract is a clouding of the ocular lens, which is the most common cause of blindness in the world [1] with 43% of the 44.8 million blind suffering from cataract [2]. Cataracts are treated by an outpatient surgical procedure that involves extracapsular cataract extraction (ECCE) followed by implantation of an artificial intraocular lens (IOL) [3, 4] This procedure is the most commonly performed outpatient surgery performed in the USA and has successfully restored the vision of over 30 million cataract patients in the USA alone. It is not possible to completely remove the lens epithelial cells (LECs) attached to the intact lens capsule, and these residual lens cells (LCs) initiate a wound healing response that includes cell proliferation, migration following surgery Some of these cells undergo an epithelial–mesenchymal transition (EMT) into migratory myofibroblasts, while others undergo lens fibre cell differentiation in an attempt to regenerate the lens [7, 8].
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