The role of cell adhesion and cytoskeleton dynamics in the pathogenesis of EDS/HSD

Project Summary

The Ehlers-Danlos syndromes (EDS) and Hypermobility Spectrum Disorders (HSD) are conditions that are not well understood. Most subtypes of EDS are caused by mutations in genes related to collagen, however, when we use microscopes to look at collagen in EDS/HSD, the abnormalities seen are relatively minor, and can also appear in the skin of people without EDS/HSD (see blog 1). Therefore, it was clear these were not the specific cause of weak connective tissue in EDS/HSD patients.

Collagen however, is not the only component of the connective tissue. There are also cells called fibroblasts which show a whole range of molecular changes in EDS/HSD, including an “integrin switch” (described in blog 2). However, it was not understood exactly how this might contribute to the weak connective tissue seen in EDS/HSD.

We performed a literature review, to better understand exactly how fibroblasts and the integrin switch might contribute to the weak connective tissue in EDS/HSD. This led us to propose an updated definition of EDS/HSD and to identify a potential diagnostic biomarker for all EDS/HSD subtypes.

“This led us to propose an updated definition of EDS/HSD and to identify a potential diagnostic biomarker for all EDS/HSD subtypes.”

Summary points from the review:

• Fibroblasts play an important role controlling the integrity of the connective tissue via a mechanism called “tensional homeostasis”. This involves fibroblasts pulling on collagen to adjust the tension within the connective tissue to maintain it at normal levels. This ability depends on two key features of fibroblasts: cell adhesion to collagen and cytoskeleton dynamics.

• Previously published experiments with EDS fibroblasts from animals found that they had a reduced cell adhesion to collagen, which caused a failure of the tensional homeostasis mechanism and resulted in fragile connective tissue in EDS animals.

• The same experiments performed with human EDS fibroblasts failed to show any abnormalities in tensional homeostasis. However, in our review, we explain how this could have been due to an experimental technicality, and may not have been reflective of their true abilities within connective tissue. 

• We further highlight how human EDS fibroblasts show equivalent impairments in cell adhesion (i.e. the “integrin switch”) to the fibroblasts from EDS animals, which was the specific molecular defect responsible for the failure of tensional homeostasis in EDS animals.
  

• We therefore propose that the same failures in tensional homeostasis occur in human EDS/HSD patients, and that further investigations are now required to test whether this is the principal mechanism responsible for EDS/HSD pathogenesis.  

We hypothesise that EDS/HSD could be a disorder of membrane-bound collagen, which occurs when fibroblasts can no longer attach to collagen. Their failure to then adequately implement the tensional homeostasis mechanism is what may then cause the abnormal connective tissue in EDS/HSD.

If this theory is correct, we suggest analysing skin biopsies for the amount of membrane-bound collagen would make an ideal diagnostic test to identify any form of EDS/HSD, since it bypasses the need of knowing the patients specific genetic basis. This is particularly important for the diagnosis of hEDS/HSD for which the genetic and molecular basis still remains elusive.

The full review can be read here.

“We hypothesise that EDS/HSD could be a disorder of membrane-bound collagen, which occurs when fibroblasts can no longer attach to collagen.”

Acknowledgments: We would like to thank Dr Gemma Pearce, Dr Emma Reinhold, and the Midlands Integrative Biosciences Training Partnership (MIBTP) funded by the Biotechnology and Biological Sciences Research Council (BBSRC), for supporting this work.

Citation: Malek, S. & Köster, DV. (2021). The role of cell adhesion and cytoskeleton dynamics in the pathogenesis of the Ehlers-Danlos syndromes and hypermobility spectrum disorders. Frontiers in Cell and Developmental Biology. Read publication.