Abstract
The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis.
Highlights
Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy
Transcriptome and in vitro analyses on Classical EDS (cEDS), Vascular EDS (vEDS), and Hypermobile EDS (hEDS)/hypermobility spectrum disorders (HSD) dermal fibroblasts expanded the knowledge about molecular mechanisms involved in the pathophysiology of these connective tissue disorders (Figure 1)
Our findings indicate that these cells share a deregulated expression of many matrix-related genes and a widespread disarray of several extracellular matrix (ECM) structural constituents, highlighting the functional relevance of a proper organization and function of the ECM in providing stability to connective tissues
Summary
Connective tissues have an extracellular matrix (ECM) with a specific composition generated during embryogenesis and maintained in adult life. The main ECM components include proteoglycans, hyaluronic acid, adhesive glycoproteins such as fibronectin and laminins, and fibrous proteins like collagens and elastin [2] Matricellular proteins such as thrombospondins, osteopontin, periostin, and tenascins are non-structural ECM proteins, primarily acting as mediators of cell–matrix interactions, which are abundantly expressed during embryonic development, wound healing, and tissues renewal [3]. Cellular fibronectin self-assembles in fibers and binds collagens, fibrin, proteoglycans, and cell surface receptors, providing cell growth, adhesion, and migration During wound healing, it forms a provisional matrix with fibrin and enters in the granulation tissue formation in the late phase of re-epithelization [11]. These bridging molecules, which are heterodimeric transmembrane receptors containing α and β subunits, connect ECM to cytoskeleton by interacting via their extracellular domain with collagens and other matrix molecules and via their cytoplasmic tails with cytoskeleton components (e.g., actin, vinculin, talin, paxillin), mediating cell adhesion and motility [14,15]
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