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Shoujun Chen, Ake Oldberg, Shukti Chakravarti, David E Birk; Down-Regulation of Fibromodulin Is Critical In Regulation of Stromal Matrix Assembly and Corneal Transparency. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4607.
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© ARVO (1962-2015); The Authors (2016-present)
Small leucine-rich proteoglycans (SLRPs) are involved in the regulation of collagen fibrillogenesis. Fibromodulin is not considered a corneal stroma SLRP, but our previous work demonstrated that fibromodulin is expressed in the stroma during early corneal development. Moreover, a significant increase in fibromodulin was consistently observed in transgenic mouse models with cloudy corneas such as a transgenic mouse model of human congenital stroma corneal dystrophy and lumican-null mice. We hypothesize that down-regulation of fibromodulin expression during corneal development is critical in regulating stromal matrix assembly and the acquisition of transparency.
Compound Fmod-/-/Lum-/-, and single Lum-/- or Fmod-/- models as well as wild type controls were utilized. SLRP expression was investigated using immuno-localization and immuno-blots. Structural relationships were defined using ultrastructural and morphometric approaches while transparency was analyzed using in vivo confocal microscopy.
The Fmod-/- mouse exhibited transparent corneas comparable to wild type corneas. No change in immuno-reactivity for SLRPs other than fibromodulin was observed in Fmod-/- corneas compared to wild type corneas. In Lum-/- corneas, fibromodulin immuno-reactivity was increased significantly compared to wild type corneas. No lumican or fibromodulin immuno-reactivity was observed in the compound Fmod-/-/Lum-/- mouse stroma. The Lum-/- corneas demonstrated mild opacity with significant opacity in the posterior stroma as shown previously. This was associated with an abnormal fibril and lamellar structure consistent with the functional deficit in transparency in the posterior stroma. In addition, fibrils had larger more heterogeneous diameters with an altered structure consistent with abnormal fibril growth. The block to fibromodulin expression in the Fmod-/-/Lum-/- stromas resulted in a stromal phenotype that was significantly mitigated compared to the Lum-/- stroma and comparable to that of Fmod-/- and wild type corneas.
The data demonstrated that blocking fibromodulin expression can rescue the corneal phenotype in lumican-null mice. This suggests that the down-regulation of fibromodulin is involved in regulating both collagen fibrillogenesis and lamellar structure necessary for transparency.
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