Molecular and cellular mechanisms of undifferentiated forms of connective tissue dysplasia (literature review)

Introduction. Undifferentiated connective tissue dysplasias include hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) (frequency ~1:500). Current treatment and diagnostics of these disorders are based on clinical aspects and do not reflect the pathogenetic features of these conditions. New insights into connective tissue disorganization open up new possibilities in search for drug target and diagnostic biomarkers.

Aim . To develop an updated model of the pathogenesis of HSD and hEDS to provide a rationale for the choiсe of potential drug targets and methods of laboratory diagnostics.

Material and methods . PubMed, Scopus, Google Scholar, and eLibrary were searched for peer-reviewed publications of 2012–2025.

Results. Transcriptomic studies revealed no significant differences between HSD and hEDS: expression of 826 genes (DNA repair, cytoskeleton) was downregulated, while expression of 126 genes (proteases, proinflammatory cytokines) was upregulated. The exception is MTHFR polymorphisms; however, different allele frequencies between HSD and hEDS have not been confirmed in cohort studies. In cell cultures, common basic mechanisms were identified, including predominance of myofibroblast differentiation via TGF-β and integrin-dependent pathways. Impaired synthetic activity of myofibroblasts leads to aberrant deposition of types I, III, and V collagen, an decrease in the number of cross-links, and intracellular accumulation of elastin. This causes extracellular matrix (ECM) degradation with formation of fragments of fibronectin (52 kDa) and type I collagen (45 kDa). ECM disruption results in fascial densification and dislocations. Based on these mechanisms, potential drug targets were identified: inhibitors of matrix metalloproteinases (MMPs) (doxycycline), folate cycle correction (5-methyltetrahydrofolate), and TGF-β signaling blockade (celiprolol).

Conclusion . No significant differences in genomic profiles or cellular metabolic activity between HSD and hEDS were found. These conditions represent a common process of connective tissue disorganization. The main pathogenetic mechanism is a vicious circle of myofibroblast activation, ECM disorganization, immune cell activation, and chronic inflammation, which further stimulates myofibroblasts. Pathogenetically justified therapeutic approaches include MMP inhibition, folate cycle correction, and TGF-β blockade. The corresponding molecules (doxycycline, 5-methyltetrahydrofolate, and celiprolol) require clinical validation.

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