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.
Highlights
Fibroblast involvement in soft connective tissue calcificationOsteopontin is a highly phosphorylated and glycosylated secreted protein originally discovered in bone, but identified in calcified vascular lesions (Giachelli et al, 1993), where it may counteract apatite deposition by physically inhibiting crystal growth (Boskey et al, 1993) and/or by up-regulating the expression of genes, as carbonic anhydrase II, favoring mineral absorption, mainly through the activation of macrophage activities (Rajachar et al, 2009)
CALCIFICATIONS IN SOFT CONNECTIVE TISSUES For long time, unwanted calcification, as that occurring in arterial calcification and in nephrolithiasis, has been considered as a passive, physical–chemical phenomenon representing a degenerative, irreversible process often associated with aging (Shroff and Shanahan, 2007)
In the last decade, a growing number of evidence is highlighting the importance of many other molecules as part of a composite network that, on the basis of common structural components, exhibits peculiar interactions and/or undergoes different regulatory mechanisms depending on the tissue [e.g., osteoprotegerin (OPG) or matrix Gla protein (MGP) in bone and vascular tissue; Kornak, 2011] and on the environmental context
Summary
Osteopontin is a highly phosphorylated and glycosylated secreted protein originally discovered in bone, but identified in calcified vascular lesions (Giachelli et al, 1993), where it may counteract apatite deposition by physically inhibiting crystal growth (Boskey et al, 1993) and/or by up-regulating the expression of genes, as carbonic anhydrase II, favoring mineral absorption, mainly through the activation of macrophage activities (Rajachar et al, 2009) These properties depend on the level of OPN phosphorylation as well as on the targeted tissue (i.e., bone or soft connective tissues; Jono et al, 2000). Heparan sulfate and dextran sulfate enhanced BMP2 activity serving as ligands to their signaling receptors on cell membranes (Takada et al, 2003)
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