In our previous blog, we talked about our current understanding of EDS/HSD and how collagen abnormalities provide a poor explanation for the weak connective tissue in EDS/HSD. Collagen, however, is not the only component of the connective tissue. There are also cells called fibroblasts in the connective tissue. One of their main roles is to make the collagen and the other proteins in the extracellular matrix (ECM) of the connective tissue.
Studies looking at the fibroblasts of EDS/HSD patients found that they also show abnormalities. The most consistent change found across all EDS/HSD subtypes involves integrins. Integrins are receptors which sit on the surface of fibroblasts. They are also called “cell adhesion molecules” because fibroblasts use these integrins to adhere to proteins in the ECM, like collagen or fibronectin.
EDS/HSD fibroblasts undergo something called an “integrin switch” (Fig. 1). Here, the collagen receptor (the α2β1 integrin) becomes internalised by the fibroblast and no longer sits on the surface. A receptor for fibronectin (the αvβ3 integrin) is upregulated, and this integrin sits on the surface of EDS/HSD fibroblasts instead.
This integrin switch occurs because collagen had not interacted with its α2β1 receptor in some way, most likely due to some structural defect in collagen. In response to this, fibroblasts decide to attach to a different ECM protein, like fibronectin, and so upregulate the αvβ3 integrin instead.
While these molecular changes are interesting, scientists do not currently understand exactly what this means or how this might contribute to weak connective tissue. This, therefore, is an area of EDS/HSD that requires further research, and is one I have specifically chosen for my PhD project (supervised by Dr Darius Köster).
More information about this project is coming soon, so keep an eye on the website and watch this space! Make sure to follow me @SabeehaMalek and @hEDStogether on Twitter so you don’t miss anything!
See you all soon!
Chiarelli, N., Ritelli, M., Zoppi, N., Colombi, M. (2019) Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes. Genes (Basel). doi:10.3390/genes10080609, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723307/
Zoppi, N., Chiarelli, N., Ritelli, M., Colombi, M. (2018) Multifaced Roles of the αvβ3 Integrin in Ehlers-Danlos and Arterial Tortuosity Syndromes’ Dermal Fibroblasts. International Journal of Molecular Sciences. doi:10.3390/ijms19040982, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979373/