Funded Research Study Update: Prof. Marina Colombi

Posted December 16, 2021

The Ehlers-Danlos Society is delighted to have provided funding as part of the Molecular Studies in hEDS and HSD $1 million grant for this research project titled, “Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD): destructuring the fibroblast secretome to define bioactive molecules and disease mechanisms, and in vivo translational studies”, with Professor Marina Colombi of University of Brescia, Brescia, Italy. The research paper was published in November of 2021, and can be viewed here.

“We are very grateful to The Ehlers-Danlos Society for funding this research project, which tried to explain the intricate protein network and molecular pathways that contribute to the effects of hypermobile Ehlers-Danlos syndrome (hEDS)”, explains Prof. Colombi.

“Our previous findings (grant number: 2018.02c.LOI.26) revealed that skin cells in individuals with hEDS change in ways that cause an extensive disruption in the extracellular matrix (ECM): in vitro cultured hEDS dermal fibroblasts undergo a fibroblast-to-myofibroblast transition, by organizing the alpha-smooth muscle actin cytoskeleton, and exhibit a widespread ECM disarray that includes collagens and fibronectin.

“In the present work, published in Cells MPDI, we compared all the proteins secreted in the culture medium of hEDS with those of control cells, and in hEDS cells we identified higher amounts of matrix metalloproteinase 1 (MMP1, an enzyme responsible for the degradation of collagens, fibronectin, and tenascins) together with lower amounts of MMP inhibitor TIMP2. This suggests that the imbalanced MMP/TIMP secretion is involved with how hEDS develops as a disorder.

“To corroborate, we treated hEDS cells with doxycycline, an FDA-approved antibiotic that acts as a nonselective MMP inhibitor. Doxycycline restored to hEDS cells an appropriate ECM organization, as well as significantly reduced their myofibroblast-like features, demonstrating that this interplay between ECM disturbance and myofibroblast differentiation is a major driver in the pathophysiology of hEDS.

“These data provide promising pathways to prevent abnormal ECM remodeling and myofibroblast differentiation and pave the way for the development of ECM-targeted therapeutic strategies in managing hEDS.”

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