Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

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.

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome

“…To study signaling pathways that could be affected by STAT3 mutations in AD-HIES during wound healing and to identify promising therapeutic targets, we performed RNA-Seq and subsequent gene set enrichment analysis (GSEA) (33) (Pathway Studio, Elsevier) and pathway-enrichment analysis (Figure 2 and Supplemental Figure 3) using primary skin fibroblasts isolated from skin biopsies of patients with AD-HIES as well as from normal control volun- abnormalities of AD-HIES patients, such as reduced ability to repair damaged lungs after infection, connective tissue abnormalities, vascular abnormalities (7-11, 13, 14), and impaired skin-wound healing (Figure 1 and Supplemental Figure 1). The relevance of the identified signaling changes to AD-HIES patients' nonimmunological features is supported by a number of hereditary connective tissue disorders with overlapping clinical presentations that are caused by mutations in ECM proteins regulated by the affected MMPs (Supplemental Figure 3, Supplemental (39,41,42).…”

“…GC designed, led, and The identification of signaling pathways related to ECM metabolism as significantly affected by AD-HIES STAT3 DN mutations (Figure 2B and Supplemental Figure 3) provides an explanation for the many similarities in presentation between AD-HIES patients and patients with other connective tissues disorders, such as Ehlers-Danlos syndromes. These syndromes are caused by genetic variants in gene-encoding collagens and collagen-modifying proteins and, similarly to AD-HIES, present with different degrees of joint hypermobility, tissue fragility, aneurisms, and defective wound healing (41,42).…”

The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders

“…In support of this relationship, particularly within the hEDS phenotype, Chiarelli et al [ 133 ] reported that while fibroblasts from classic and vascular EDS patients displayed perturbed collagen biosynthesis and processing, hEDS fibroblasts were typified by a pro-inflammatory myofibroblast-like state, suggesting a process of chronic abnormal wound repair. Therefore, the originating cause in many cases of hEDS may be upstream of collagen synthesis and mediated by the immune system.…”

The Role of Cell Adhesion and Cytoskeleton Dynamics in the Pathogenesis of the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders

“…The culturing of fibroblasts derived from the dermal biopsies of EDS/HSD patients have revealed several relevant molecular changes ( Zoppi et al, 2018b ; Chiarelli et al, 2019 ), including an altered integrin expression profile that is shared amongst the main EDS/HSD subtypes ( Zoppi et al, 2018b ). Integrins are cell surface receptors composed of one α and one β subunit, giving rise to 24 unique integrins which play a central role in cell adhesion, cell signaling, and cell survival ( Barczyk et al, 2010 ).…”