Updated project metadata. Pseudoxanthoma elasticum (PXE) is characterized by ectopic calcification, however, despite the widely spread effect of pro/anti-calcifying systemic factors associated with the genetic metabolic condition, it not known why elastic fibers (EF) in the same patient are mainly fragmented or highly mineralized in clinically unaffected (CUS) and affected (CAS) skin, respectively. Cellular morphology and secretome were investigated in vitro in CUS and CAS fibroblasts. Data reveal that in CAS fibroblasts focal adhesions and stress fibers are differently distributed and organized thus affecting cell-matrix interactions (i.e., collagen gel retraction). These changes are known to influence the extracellular matrix (ECM) and the signals provided to cells. Differentially expressed secreted proteins (e.g., altered balance of MMPs/TIMP, of pro-/anti-calcifying proteoglycans, of elastic-fibers associated glycoproteins) may alter the stability of EF and the ECM milieu, creating local microenvironments guiding the level of matrix remodeling at an extent that may lead to degradation (in CUS) or to degradation and calcification (in CAS) of the elastic component, further highlighting the active role of fibroblasts and of ECM in pathologic mineral deposition.