Pseudoexfoliation Syndrome: New Insights Provided by Molecular Biologic Research

Schlötzer-Schrehardt U., Zenkel M., Naumann G. O. H.,
Friedrich-Alexander-Universität, Augenklinik (Erlangen)

Purpose: Pseudoexfoliation (PEX) syndrome is a genetically determined generalized disorder of the extracellular matrix of unknown etiology, which is characterized by the increased production and accumulation of an abnormal extracellular material in intra- and extraocular tissues. Due to deposition of the aberrant matrix product in the trabecular meshwork and in blood vessel walls, PEX syndrome represents a significant risk factor for the development of secondary open-angle glaucoma and for ocular and systemic vascular complications. In order to elucidate the molecular causes of this matrix disorder, we analyzed the gene expression profile in tissues of PEX patients.
Methods: Various experimental approaches for the analysis of differential gene expression in tissues of PEX and control patients comprised cDNA arrays, subtractive hybridization and differential screening, Northern blots, RT-PCR, and in situ hybridization.
Results: The differential gene expression analysis so far showed about 50 differentially expressed genes in PEX tissues, which included matrix components (e.g. fibrillin-1, LTBP-1), matrix-associated enzymes (e.g. transglutaminase-2, matrix metalloproteinases and their inhibitors TIMPs), growth factors (e.g. TGF-ß1), signal transduction molecules (e.g. MAP kinase), cellular stress markers (e.g. heat shock proteins, apolipoprotein D, clusterin), oxidative stress markers (e.g. 8-isoprostane-F2a, glutathione-S-transferase, glutathione peroxidase), and DNA repair proteins (e.g. hmlh1). Based on these findings, we established a pathogenetic concept describing PEX syndrome as a special form of an elastosis accompanied by an increased production of elastic microfibrils by a broad spectrum of potentially elastogenic cells. Overexpression of TGF-ß1, a disbalance of metalloproteinases and TIMPs, excessice cross linking processes, and increased oxidative stress appear to be causally involved in pathogenesis.
Conclusions: The molecular biologic analysis of the gene expression profile in tissues of PEX patients led to a better understanding of the underlying pathogenetic principles and to the identification of disease-related key molecules (e.g. TGF-ß1, TIMP-1) that may be helpful as diagnostic and prognostic parameters or as future therapeutic targets.

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