elastin and Homocystinuria

Several inherited syndromes characterized by abnormal elastic fibers decreased in number and size could be collected under the heading of inherited elastolysis. This morphological concept does not prejudge the causal mechanisms of the elastolysis involving dermis and/or other organs. The elastic fibers anomalies result mainly from elastin crosslinking defects, developmental disturbances or excessive proteolysis.

Topics: alpha 1-Antitrypsin Deficiency; Ehlers-Danlos Syndrome; Elastin; Homocystinuria; Humans; Marfan Syndrome; Menkes Kinky Hair Syndrome; Skin; Skin Diseases

It is apparent that significant progress has been made in our understanding of the biosynthesis, modifications, and maturation of collagen and elastin. We now recognize and partially understand special reactions involved in hydroxylations within the cell and complex cross-linking processes occurring outside the cell. Recent experiments (191) have shown that in human diploid fibroblast cultures of limited doubling potential (191) the hydroxylation of collagen prolyl residues appears to be "age" or passage-level dependent. With increasing passage level of these cultures, both the ascorbate requirements and the extent of collagen hydroxylation decrease. "Young" cell cultures have a strong requirement for complete hydroxylation and without ascorbate there is only about 50% of the normal level. "Middle-aged" cultures show higher hydroxylation without and full hydroxylation with ascorbate, whereas "old" (or cultures close to "senescence") are incapable of full hydroxylation with or without ascorbic acid. Although the overall system may show some deterioration with increasing passage levels, it appears that with increasing passage levels other components in the cell replace the ascorbate dependence of the hydroxylase system to a greater exten. In some ways, aging WI-38 cultures begin to resemble some transformed cells in their biochemical reactions, although they continue to remain diploid and eventually lose the ability to replicate. It is not yet known whether old animals can produce collagen, which may now be underhydroxylated, perhaps contributing to certain senescent changes. Careful examination of the hydroxylation index of collagen produced in organoid cultures of tissue biopsies as a function of donor age might be informative, particularly if one looks at the quality of collagen by employing collagenase and other proteolytic digests with collagen (191). One could comare the levels of frequent and characteristic peptide triplet sequences such as Gly-Pro-Hyp to Gly-Pro-Pro, Gly-Ala-Hyp to Gly-Ala-Pro, or Gly-Pro-Hyl to Gly-Pro-Lys and others for evaluation of hydroxylation throughout the entire molecule or at selected sequences.

Topics: Amino Acid Sequence; Animals; Antibody Specificity; Ascorbic Acid; Collagen; Connective Tissue; Copper; Ehlers-Danlos Syndrome; Elastin; Epitopes; Homocystinuria; Humans; Hydralazine; Lathyrism; Marfan Syndrome; Molecular Conformation; Platelet Aggregation; Procollagen-Proline Dioxygenase; Skin Diseases; Syndrome

Young growing rats were intraperitoneally injected with mixtures of homocystine and methionine for several weeks. The growth of the animals was inhibited. After 3 weeks 25% of the rats died and isolation of tail tendon collagen and aorta elastin showed that these proteins were deficient in chemical cross-links. Seventy-five % of the rats survived further injections for another 3 weeks and isolated collagen and elastin were found to be normal in cross-linking. The variability in susceptibility of these rats to homocystine-methionine treatment is discussed in relationship to human homocystinuria. It is speculated that the variability is due to variability in in vivo homocysteine levels.

Topics: Animals; Collagen; Connective Tissue; Disease Models, Animal; Elastin; Female; Homocystine; Homocystinuria; Humans; Male; Methionine; Peptides; Rats; Solubility