Abstract
PurposeTo investigate whether the Sonic hedgehog (Shh) signaling induces myopic development by increasing the expression of matrix metalloproteinase (MMP)-2 in guinea pigs.MethodsA translucent diffuser was glued onto the right eye to induce form-deprivation myopia (FDM) in 10 guinea pigs. Four guinea pigs were served as a control group. The other 100 guinea pigs were subdivided into 5 groups (20 per group) and received a 10 µl intravitreal injection every 2 days for 4 times. Two groups were injected with 20 or 50 µg/ml Shh amino-terminal peptide (Shh-N) into the right eye and 0.1% bovine serum albumin into the other. FDM was induced in the right eyes of the three cyclopamine-treated groups and both eyes were injected with 50, 100, or 200 µg/ml cyclopamine. Retinoscopic refraction and eye dimensions were assessed on Day 14 of treatment. MMP-2 protein expression was determined in both scleras by western blotting.ResultsBoth concentrations of Shh-N stimulated myopic development and axial growth as compared with control eyes. Myopia and axial elongation were significantly greater in the 50 µg/ml than in the 20 µg/ml Shh-N group (P<0.001 and P = 0.0019, respectively). All three doses of cyclopamine significantly attenuated myopic development compared with the FDM group (P<0.0001). Cyclopamine at 100 or 200 µg/ml significantly reduced axial elongation compared with the FDM group (P = 0.044 and P = 0.001, respectively). FDM-induced myopia and axial elongation were significantly greater in the 50 µg/ml than in the 200 µg/ml cyclopamine group (P<0.0001 and P = 0.008, respectively). MMP-2 expression was significantly greater in Shh-N–treated eyes than in the control eyes, and was lower in the cyclopamine plus FDM groups than in the FDM group.ConclusionsThe Shh signaling pathway induces myopic development by activating MMP-2 in guinea pigs.
Highlights
Myopia is a major public health concern and there is striking evidence for a rapid increase in its prevalence in recent years [1]
It was reported that the expression and activity of matrix metalloproteinase (MMP)-2 were enhanced by exogenous Sonic hedgehog (Shh) and were inhibited by blocking Shh signaling with a Shh neutralizing antibody or cyclopamine in hepatocellular carcinoma samples [16]. These results suggest that Shh might induce myopic development by enhancing the expression and activity of MMP-2 in animal models of myopia
The right eyes in the form-deprivation myopia (FDM) and both Shh-treated groups exhibited significant myopia and axial elongation compared with the left contralateral eyes at the end of observation, whereas there were no differences between the left and right eyes in the control group (Table 3)
Summary
Myopia is a major public health concern and there is striking evidence for a rapid increase in its prevalence in recent years [1]. Animal models have enabled significant advances in our understanding of the refractive development and the regulation of eye growth during myopic development. Animal models of myopia have revealed that visually guided eye growth is regulated by several retinal substances, including vasoactive intestinal peptide [2], dopamine [3], retinoic acid [4], early growth response gene-1 ( called ZENK in chickens) [5], and Sonic hedgehog (Shh) [6,7,8]. Current theories of refractive development acknowledge the pivotal role of the sclera in the control of eye size and in myopic development. It has been speculated that there is a local retinoscleral signaling cascade that regulates the expression of modulators in the sclera and controls scleral remodeling during myopic development [11]
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