Our human lens capsular bag model illustrated that addition of active TGFβ2 following sham cataract operations resulted in anterior lens epithelial cell migration, matrix contraction, and wrinkle formation. These events are hallmarks of PCO.
3,11 However, the addition of an MMP2 inhibitor not only prevented wrinkle formation but cells found on the posterior capsule in capsular bags treated with TGFβ2 and MMP2 neutralizing antibody exhibited a morphology characteristic of anterior cuboidal lens epithelial cells. Furthermore, progression of anterior lens epithelial cells exposed to TGFβ2 and MMP2 antibody on to the posterior capsule was attenuated compared to capsular bags treated with TGFβ2 alone. These findings are comparable to a study by Wong et al.
48 in which donor human capsular bag cultures were treated with 10% serum supplemented media in the presence and absence of the broad-spectrum MMP inhibitor GM6001 . Following GM6001 (100 μM) treatment for 10 days a 5-fold difference in cell migration was observed compared to controls, along with minimal capsular wrinkling. By day 15 only 5% capsular contraction was exhibited in GM6001-treated cultures, whilst a 60% capsular contraction was detected in cultures maintained in control conditions.
48 Additionally, Seomun et al.
49 determined that human lens epithelial cells (HLE B3s) treated with (2
R)-2-[(4-biphenylylsulfonyl)amino]-3-phenylpropionic acid (a MMP2/9 inhibitor) in the presence of TGFβ1 prevented the elongated and scattered cell morphology associated with TGFβ1 treatment. Furthermore, strong immunoreactivity for αSMA and MMP2 was correlated with TGFβ1-induced anterior subcapsular plaque formation.
49 Our findings could be due to several factors that are influenced by MMP2. The ECM is an excellent store of bound growth factors including TGFβ,
35,36 along with other growth factors such as fibroblast growth factor (FGF)
50 and insulin growth factor (IGF).
51 This accrual of growth factors can provide a considerable reserve of bioavailable cytokines under appropriate conditions, which can exacerbate TGFβ effects in the capsular bag. For example, in a whole rat-lens study of anterior subcapsular plaque formation, FGF was found to significantly enhance the effects of TGFβ-induced ASC; however, FGF alone was incapable of instigating plaque formation.
52 FGF is, however, an inducer of lens cell proliferation.
53,54 In our capsular bags treated with TGFβ2 and MMP2 inhibitor, the lack of active MMP2 production could also be inhibiting FGF release from the collagenous capsule, thus preventing subsequent stimulation of anterior lens cell proliferation and migration.