Collagen Network Formation in In Vitro Models of Musculocontractural Ehlers-Danlos Syndrome.

Loss-of-function mutations in carbohydrate sulfotransferase 14 ( CHST14 ) cause musculocontractural Ehlers-Danlos syndrome- CHST14 (mcEDS- CHST14 ), characterized by multiple congenital malformations and progressive connective tissue fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral and ocular system. The replacement of dermatan sulfate chains on decorin proteoglycan with chondroitin sulfate chains is proposed to lead to the disorganization of collagen networks in the skin. However, the pathogenic mechanisms of mcEDS- CHST14 are not fully understood, partly due to the lack of in vitro models of this disease. In the present study, we established in vitro models of fibroblast-mediated collagen network formation that recapacitate mcEDS- CHST14 pathology. Electron microscopy analysis of mcEDS- CHST14 -mimicking collagen gels revealed an impaired fibrillar organization that resulted in weaker mechanical strength of the gels. The addition of decorin isolated from patients with mcEDS- CHST14 and Chst14 -/- mice disturbed the assembly of collagen fibrils in vitro compared to control decorin. Our study may provide useful in vitro models of mcEDS- CHST14 to elucidate the pathomechanism of this disease.