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

Abstract

The Ehlers-Danlos syndromes (EDS) are a group of 13 disorders, clinically defined through features of joint hypermobility, skin hyperextensibility, and tissue fragility. Most subtypes are caused by mutations in genes affecting the structure or processing of the extracellular matrix (ECM) protein collagen. The Hypermobility Spectrum Disorders (HSDs) are clinically indistinguishable disorders, but are considered to lack a genetic basis. The pathogenesis of all these disorders, however, remains poorly understood. Genotype-phenotype correlations are limited, and findings of aberrant collagen fibrils are inconsistent and associate poorly with the subtype and severity of the disorder. The defective ECM, however, also has consequences for cellular processes. EDS/HSD fibroblasts exhibit a dysfunctional phenotype including impairments in cell adhesion and cytoskeleton organization, though the pathological significance of this has remained unclear. Recent advances in our understanding of fibroblast mechanobiology suggest these changes may actually reflect features of a pathomechanism we herein define. This review departs from the traditional view of EDS/HSD, where pathogenesis is mediated by the structurally defective ECM. Instead, we propose EDS/HSD may be a disorder of membrane-bound collagen, and consider how aberrations in cell adhesion and cytoskeleton dynamics could drive the abnormal properties of the connective tissue, and be responsible for the pathogenesis of EDS/HSD.

Biomechanical changes in the gastrocnemius medius–Achilles tendon complex in people with hypermobility spectrum disorders: A cross-sectional compression sonoelastography study

“… The higher the strain ratio, the higher the elasticity of the examined structure ( 37 ). GM, gastrocnemius medius muscle, AT, Achilles tendon, CI, confidence interval.…”

“…However, the genetic etiology of HSD is not yet conclusive and is sometimes contradictory. The etiology has also been related to abnormalities in an extracellular glycoprotein (tenascin-X), which bridges between collagen fibers and contributes toward collagen formation, and in fibroblast mechanobiology of cell adhesion and cytoskeleton organization ( 20 , 37 ). The abnormalities of vital components of the connective tissues in HSD could explain the significant reduction in the strain ratio of the GM-AT complex identified by the current study.…”

Genomic Characterization by Whole-Exome Sequencing of Hypermobility Spectrum Disorder

“…In addition, other GO terms, such as cell adhesion molecule binding and cytoskeleton motor activity, were overrepresented. Recently, it has been proposed that aberrations in cell adhesion and cytoskeleton dynamics could drive the abnormal properties of the connective tissue and be responsible for the pathogenesis of HSD/EDS [ 58 ]. In this sense, DSP , an adhesion molecule-encoding gene identified with only one mutation in our list of mutated genes in patients diagnosed with HSD became relevant.…”

Mechanobiology in the Comorbidities of Ehlers Danlos Syndrome

“…Each EDS subclass is associated with stretchiness or rupture of skin and artery or hypermobility of joint ( Bowen et al, 2017 ; Brady et al, 2017 ; Byers et al, 2017 ; Tinkle et al, 2017 ; Blackburn et al, 2018 ). Despite identified genetic defects, molecular explanation of how the genetic defects lead to clinical phenotypes that are assessed for EDS subclass determination has been unclear ( Malek and Köster, 2021 ). Since defected genes are related to collagen formation, it has been assumed that microarchitectural changes due to those genetic defects can give rise to clinical abnormality exhibited in the EDS patients ( Kobayasi, 2004 ).…”

“…For example, changes in adhesion and cytoskeletal organization, key mediators for mechanotransduction, are observed, along with defects in migration and contractility, in dermal fibroblasts from cEDS, hEDS and vEDS ( Viglio et al, 2008 ; Zoppi et al, 2018 ). How EDS affects fibroblast dysfunction has been well discussed in a recent review article ( Malek and Köster, 2021 ). However, how extracellular changes in EDS, particularly in the two most common types, hypermobile type (hEDS) and classical type (cEDS), can promote comorbidities of EDS have just begun to be revealed.…”