Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder which is caused by ABCC6 (ATP-binding cassette subfamily C member 6) gene mutations. Characteristic hallmarks of PXE are progressive calcification and degradation of the elastic fibers in skin, cardiovascular system and ocular fundus. Since the underlying pathomechanisms of PXE remain unidentified, the aim of this study was to get new insights into PXE pathophysiology by characterizing dermal myofibroblast differentiation. Fibroblasts are the key cells of extracellular matrix (ECM) remodeling and, therefore, participate not only in physiological processes, such as calcification or wound healing, but also in pathologic events, such as fibrotization. We revealed that human dermal PXE fibroblasts possess exaggerated migration capability in wound healing and attenuated myofibroblast contractility in comparison to controls. Subsequent analyses reinforced these observations and indicated a diminished induction of the myofibroblast differentiation markers α-smooth muscle actin and xylosyltransferase-I as well as poor transforming growth factor-β1 responsiveness in PXE fibroblasts. In summary, we describe pathological deviations of dermal myofibroblast differentiation in PXE which might be mediated by aberrant supramolecular ECM organization. These results not only improve our insights into cellular PXE pathophysiology, but might also qualify us to interfere with ECM remodeling in the future.
Keywords: Connective tissue; Extracellular matrix; Myofibroblast differentiation; Pseudoxanthoma elasticum; Wound healing; Xylosyltransferase.
Copyright © 2017 Elsevier Inc. All rights reserved.