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Laboratory Investigation (2007) 87, 9981008 & 2007 USCAP, Inc All rights reserved 0023-6837/07 $30.00
Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients
Dealba Gheduzzi1,*, Federica Boraldi1,*, Giulia Annovi1, Chiara Paolinelli DeVincenzi1, Leon J Schurgers2, Cees Vermeer2, Daniela Quaglino1 and Ivonne Pasquali Ronchetti1
Mature MGP (Matrix g-carboxyglutamic acid protein) is known to inhibit soft connective tissues calcification. We investigated its possible involvement in pseudoxanthoma elasticum (PXE), a genetic disorder whose clinical manifestations are due to mineralization of elastic fibers. PXE patients have lower serum concentration of total MGP compared to controls (Po0.001). Antibodies specific for the noncarboxylated (Glu-MGP) and for the g-carboxylated (Gla-MGP) forms of MGP were assayed on ultrathin sections of dermis from controls and PXE patients. Normal elastic fibers in controls and patients were slightly positive for both forms of MGP, whereas Gla-MGP was more abundant within controls than within patients elastic fibers (Po0.001). In patients calcified elastic fibers, Glu-MGP intensively colocalized with mineral precipitates, whereas Gla-MGP precisely localized at the mineralization front. Data suggest that MGP is present within elastic fibers and is associated with calcification of dermal elastic fibers in PXE. To investigate whether local cells produce MGP, dermal fibroblasts were cultured in vitro and MGP was assayed at mRNA and protein levels. In spite of very similar MGP mRNA expression, cells from PXE patients produced 30% less of Gla-MGP compared to controls. Data were confirmed by immunocytochemistry on ultrathin sections. Normal fibroblasts in vitro were positive for both forms of MGP. PXE fibroblasts were positive for Glu-MGP and only barely positive for Gla-MGP (Po0.001). In conclusion, MGP is involved in elastic fiber calcification in PXE. The lower ratio of Gla-MGP over Glu-MGP in pathological fibroblasts compared to controls suggests these cells may play an important role in the ectopic calcification in PXE.
Laboratory Investigation (2007) 87, 9981008; doi:10.1038/labinvest.3700667; published online 27 August 2007
KEYWORDS: calcification; dermal fibroblast; elastic fiber; human skin; MGP; pseudoxanthoma elasticum The high concentration of calcium and phosphate in the extracellular space would lead to tissue calcification unless efficiently inhibited by a series of proteins and glycoproteins that have been found to operate in soft connective tissues toprevent calcium precipitation.1
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