ABNORMAL FORMATION OF COLLAGEN CROSS-LINKS IN SKIN FIBROBLASTS CULTURED FROM PATIENTS WITH EHLERS-DANLOS SYNDROME TYPE-VI

Ehlers-Danlos syndrome type VI (EDS VI) is an autosomal recessive diso rder of connective tissue characterized by hyperextensible, friable sk in and joint hypermobility. Severe scoliosis and ocular fragility are present in some patients. This disease is caused by defective collagen lysyl hydroxylase, a vitamin C-dependent enzyme that converts lysyl r esidues to hydroxylysine on procollagen peptides. Hydroxylysine is ess ential for the formation of the covalent pyridinium cross-links pyridi noline (Pyr) and deoxypyridinoline (Dpyr), among mature collagen molec ules. Pyr derives from three hydroxylysyl residues, whereas Dpyr deriv es from one lysyl and two hydroxylysyl residues. Patients with EDS VI have high urinary excretion of Dpyr, resulting in a high ratio of Dpyr -Pyr. In this study, we evaluate content and production of pyridinium cross-links in the skin and cultured fibroblasts from patients with ED S VI. The skin of normal controls contained both Pyr and Dpyr, with a marked predominance of Pyr as observed in normal urine. The skin of pa tients with EDS VI had reduced total content of pyridinium cross-links , with the presence of Dpyr but not Pyr. Long-term cultures of control fibroblasts produced both Pyr and Dpyr, with a pattern resembling tha t of normal skin. By contrast, cross-link were not detected in dermal fibroblasts cultured from patients with EDS VI. Vitamin C, which impro ves the clinical manifestations of some patients with EDS VI, decrease d Dpyr accumulation though only minimally affecting Pyr content in con trol cells. By contrast, addition of vitamin C to fibroblasts from pat ients with EDS VI stimulated the formation of Dpyr more than that of P yr and greatly increased total pyridinium cross-link formation. These results indicate that qualitative and quantitative alterations of pyri dinium cross-links occur in skin and in cultured dermal fibroblasts of patients with EDS VI and may be responsible for their abnormal skin f indings. The vitamin C-stimulated production of Dpyr and Pyr in fibrob lasts from patients with EDS VI may explain at least in part the thera peutic effects of this vitamin in EDS VI.