Fibroblast involvement in soft connective tissue calcification

Ivonne Ronchetti, Federica Boraldi, Giulia Annovi, Paolo Cianciulli, Daniela Quaglino, Ivonne Ronchetti, Federica Boraldi, Giulia Annovi, Paolo Cianciulli, Daniela Quaglino

Abstract

Soft connective tissue calcification is not a passive process, but the consequence of metabolic changes of local mesenchymal cells that, depending on both genetic and environmental factors, alter the balance between pro- and anti-calcifying pathways. While the role of smooth muscle cells and pericytes in ectopic calcifications has been widely investigated, the involvement of fibroblasts is still elusive. Fibroblasts isolated from the dermis of pseudoxanthoma elasticum (PXE) patients and of patients exhibiting PXE-like clinical and histopathological findings offer an attractive model to investigate the mechanisms leading to the precipitation of mineral deposits within elastic fibers and to explore the influence of the genetic background and of the extracellular environment on fibroblast-associated calcifications, thus improving the knowledge on the role of mesenchymal cells on pathologic mineralization.

Keywords: PXE; PXE-like disorders; ectopic calcification; elastin; extracellular matrix; fibroblasts; mesenchymal stromal cells.

Figures

FIGURE 1
FIGURE 1
Major factors involved in mineral deposition. AMP, adesosine monophosphate; ANKH, ankylosis protein homolog; ATP, adenosine triphosphate; BMP2, bone morphogenetic protein-2; BMP2R, bone morphogenetic protein-2 receptor; BSP, bone sialoprotein; Ca, calcium; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase; Glu- and Gla-MGP, uncarboxylated- and carboxylated-matrix Gla protein; OPG, osteoprotegerin; OPN, osteopontin; Pi, inorganic phosphate; Pit-1, phosphate transporter-1; PPi, pyrophosphate; RANKL, receptor activator of nuclear factor kappa-B ligand; TNAP, tissue non-specific alkaline phosphatase.
FIGURE 2
FIGURE 2
Transmission electron microscopy of a dermal biopsy from a patient affected by pseudoxanthoma elasticum (PXE). Deformed calcified elastic fibers (E) are present in close proximity to large fibroblasts with abundant and dilated cisternae of the endoplasmic reticulum. Collagen fibrils occasionally organized into collagen flowers (arrows) are also visible. Bar = 1 μm.
FIGURE 3
FIGURE 3
Light microscopy of dermal fibroblasts cultured for 3 weeks in the presence of DMEM (A) or of DMEM supplemented with ascorbate, beta-glycerophosphate, and dexamethasone (B). In the presence of the calcified medium, dermal fibroblasts exhibit areas of mineralization that can be clearly visualized upon Von Kossa staining as dark deposits (lower panel; see also Boraldi et al., in press, for methodological details).
FIGURE 4
FIGURE 4
Calcein uptake and extrusion in cultured fibroblasts from healthy individuals (Control), PXE patients (PXE), beta-Thalassemic patients with (βThal/PXE) and without (βThal) PXE-like manifestations. Intracellular calcein accumulation is shown after 2 and 30 min by confocal microscopy (A). Calcein uptake (B) and extrusion (C) have been measured by flow cytometry and are shown in panels on the right (see also Boraldi et al., 2003, for methodological details).

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