Abstract
Fibroblasts from young patients exhibiting clinical features of progeroidal syndromes showed decreased biosynthesis of the small proteoglycan decorin. Cells in culture were metabolically labeled, and proteoglycans secreted into the medium were analyzed electrophoretically after immunoprecipitation with antibodies raised against decorin and biglycan. Fluorograms showed regularly a reduction to 15-30% of the normal amount of mature decorin and its core protein after chondroitin ABC lyase treatment. The size of the glycosaminoglycan chains was increased, but there was no obvious anomaly in the secretion kinetics of the mature proteoglycan. In addition, the patients' fibroblasts synthesized an increased amount of biglycan compared to control cells from healthy donors. Northern blot analysis clearly demonstrated a reduction by 85-94% in decorin mRNA, but biglycan mRNA was concomitantly increased, indicating that these alterations occur at the transcriptional level of protein expression. Transcription of decorin in fibroblasts from one of the patients was stimulated up to 3-fold by treatment with interleukin-1 beta. No response to interleukin-1 beta and transforming growth factor-beta was observed in the cells from another patient. In situ hybridization of cultured cells with an antisense decorin probe showed that decorin levels were reduced throughout the cell population. Surprisingly, subsequent examination of cells from one of the patients, now in mid-teenage, revealed a return to normal levels of decorin expression compared to age-matched controls. These studies suggest that, as in Marfan's syndrome where the primary defect concerns the fibrillin gene, reduced decorin expression contributes to the formation of an abnormal matrix and the pathogenesis of these disorders. They also indicate that this abnormality is likely to represent a secondary phenomenon which leads to a fault in the regulation of decorin gene transcription.
Highlights
The extracellular matrix can be considered as a collection features of progeroidal syndromes showed decreased of macromolecules surrounding the cells and comprisinga biosynthesis of the small proteoglycan decorin
The patients’ fibro- according to the size of the core proteins, members of both blastssynthesized an increasedamount of biglycan classes are abundant in the extracellular matrix of various compared to control cells from healthy donors
The secreted form of the second member is comprised of a coreprotein M, = 36,319 [10]with a single glycosaminoglycacnhain linked to the serine residue at position 4 [11].Its name decorin derives from the observationthatitbinds,throughits core protein,tothe surface of collagen fibrils, both i n vivo and i n vitro [12,13,14,15]
Summary
Div. of Pediatrics, University of Ghent, Ghent, Belgium. ++ T o whom correspondence shouldbe addressed. We have previously described a patient who represented a progeroid variant with signs of the Ehlers-Danlos syndrome [29]. His cultured fibroblasts exhibited defective small proteoglyca~biosynthesis due to an abnorma~ly thermolabile galactosyltransferase I [30], an enzyme which catalyzes the second glycosyl transfer reaction in the assembly of xylose/serine-linked proteoglycans. No similar deficiency was detected when several other fibroblast cell lines from patients with a progeroid phenotype were analyzed. Instead, they could be characterized by a transcriptional defect of decorin expression and by an overexpression of biglycan. Evidence will bepresented that at least in one patient theabnormality is in the regulation of decorin gene transcription and not in the decorin gene itself
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
