elastin and Progeria

Elastin is rapidly deposited during late gestation in resilient tissues such as the arteries, lungs and skin owing to increased concentration of its mRNA. Pathological states can arise from congenital insufficiency or disorganization of elastin (cutis laxa). Other elastin deficiencies may be due to excess elastolysis or gene dosage effects. In the former, high turnover rates can be assessed by measurements of elastin degradation products in urine. Excess elastin accumulation by skin fibroblasts is characteristic of genetic diseases such as Buschke-Ollendorff syndrome, Hutchinson-Gilford progeria and keloid. Elastin expression is modulated by peptide growth factors, steroid hormones and phorbol esters, among which transforming growth factor beta (TGF-beta) is an especially potent up-regulator, acting largely through stabilization of mRNA. Recent evidence indicates cutis laxa fibroblasts that express little or no elastin have normal transcriptional activity but abnormal rates of elastin mRNA degradation. This defect is substantially reversed by TGF-beta through mRNA stabilization. Current studies explore the hypothesis that stability determinants lie within the 3' untranslated region of elastin mRNA. Post-transcriptional control of elastin expression appears to be a major regulatory mechanism.

Topics: Animals; Cutis Laxa; Elastin; Fibrosis; Humans; Keloid; Progeria

Several "progeroid" syndromes have now been identified. The De Barsy syndrome is an autosomal recessive syndrome of dwarfism, mental deficiency, an "aged" appearance at birth, abnormal elastic fibers on skin biopsy, and lax skin, large helices, eye abnormalities, lax joints, hypotonia, and athetoid posturing. We report one case and review 11 cases from the literature. To understand the abnormal appearance of the elastic fibers on biopsy, we performed elastin gene expression studies on fibroblasts cultured from our patient's skin. Molecular hybridization studies revealed reduced elastin mRNA steady-state levels as compared with age matched control individuals. Assuming normal rates of mRNA translation, reduced elastin synthesis would occur. Diminished dermal elastin content could explain the altered cutaneous elasticity, decreased elastic fibers in the skin, and many clinical manifestations of individuals with this condition.

Topics: Child, Preschool; Diagnosis, Differential; Elastin; Female; Gene Expression; Humans; Phenotype; Progeria; RNA, Messenger; Skin; Syndrome

We have been concerned in the first section of this review with those diseases that are aging processes, or appear to be so. Some of these (e.g., cardiovascular, pulmonary, neoplasia) cause the death of a large proportion of animals, while others (e.g., osteoporosis, amyloidosis), though clearly progressive with age, are nonfatal. Many diverse factors influence the normal process of aging. Restriction of dietary caloric intake prolongs lifespan and decreases the incidence and severity of diseases associated with aging, probably by depressing anterior pituitary gland function...

Topics: Aging; Animals; Antioxidants; Cells; Collagen; Diet; Disease Models, Animal; Elastin; Hormones; Humans; Immune System Diseases; Mice; Models, Biological; Pigmentation; Progeria; Radiation Effects; Rats; Stress, Physiological; Stress, Psychological; Vitamin D

Topics: Animals; Basement Membrane; Cattle; Collagen; Connective Tissue; Ehlers-Danlos Syndrome; Elastin; Epidermolysis Bullosa; Fibroblasts; Glycopeptides; Humans; Keloid; Lysine; Marfan Syndrome; Metabolism, Inborn Errors; Microbial Collagenase; Mixed Function Oxygenases; Progeria; Protein Biosynthesis; Pseudoxanthoma Elasticum; Wound Healing

In 1968, De Barsy reported on a girl exhibiting an aged aspect, 'dwarfism, oligophrenia, and degeneration of the elastic tissue in cornea and skin'. The disorder was recognized as a subgroup of cutis laxa syndrome and termed De Barsy-Moens-Dierckx syndrome. The pathogenesis of the disorder is unknown.. To improve the comprehension of the pathogenetic mechanisms involved in the De Barsy syndrome, we performed an ultrastructural, morphometric, immunocytochemical study on a skin biopsy of a boy with the De Barsy phenotype, who has been clinically followed for 12 years from birth. Moreover, the lysyl oxidase activity was measured on skin fibroblasts cultured in vitro.. Light and electron microscopy, morphometry, and immunocytochemical observations showed a significant reduction of the elastic fibers in the papillary and in the reticular dermis of patient compared to an age-matched control (p < 0.05). By contrast, the collagen structure, content, and the distribution were normal, as well as lysyl oxidase activity in the medium of in vitro fibroblasts (12,323 DPM/10(6) cells). The immunoreaction for antibodies recognizing fibrillin-1, neutrophilic elastase, and tumor necrosis factor-alpha was stronger, whereas that for antibodies against transforming growth factor-beta was less pronounced in the dermis of the De Barsy boy compared to control.. Clinical, phenotypic, and structural data were consistent with the diagnosis of De Barsy syndrome. This is the first case described in Italy. Clinical and structural data confirm that the elastic component is mostly affected in this disorder. Moreover, ultrastructural and immunochemical findings suggest that both elastic fiber degradative and very likely synthetic processes are involved.

Topics: Abnormalities, Multiple; Cells, Cultured; Child; Child, Preschool; Elastin; Fibroblasts; Humans; Immunohistochemistry; Infant; Infant, Newborn; Male; Microscopy, Electron; Progeria; Protein-Lysine 6-Oxidase; Skin; Skin Abnormalities; Syndrome

Topics: Adolescent; Child, Preschool; Collagen; Elastin; Humans; Hyaluronic Acid; Male; Progeria; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Adolescent; Cerebral Arteries; Collagen; Death, Sudden; Elastin; Female; Humans; Progeria

Elastin and type IV collagen production are markedly elevated in fibroblasts derived from the skin of patients with Hutchinson-Gilford progeria (HGP). Fibroblasts from three affected children and their parents were compared to normal human skin fibroblasts with respect to elastin production as a function of different concentrations of calf serum and the cytokines, transforming growth factor-beta and basic fibroblast growth factor (TGF-beta 1, bFGF). In cultured fibroblasts from the parents of probands that were very high elastin producers (> 10(5) molecular equivalents/cell per h), at least one parent (mother) presented the same phenotype. Overproduction of elastin in culture could have been due to increased sensitivity of HGP strains to stimuli present in serum; however, relative stimulation of elastin production by calf serum in cell strains from HGP elastin over-producers was less than half the control strain. In most of the cultures examined, the responsiveness of elastin production to TGF-beta 1 was almost absent when compared to the response of normal fibroblasts. HGP strains with high elastin production modified conditioned medium to enhance elastin production in normal cells. These results suggest the presence, in HGP skin fibroblasts, of inheritance of high elastin production that is associated with accelerated aging.

Topics: Adolescent; Adult; Cells, Cultured; Child; Elastin; Female; Fibroblast Growth Factor 2; Fibroblasts; Humans; Infant; Male; Phenotype; Progeria; Skin; Skin Physiological Phenomena; Transforming Growth Factor beta

The Hutchinson-Gilford syndrome (progeria) is a rare disorder in childhood characterized by premature and accelerated aging. This study reports the effect of a potent growth factor, EGF, on the proliferative capacities and extracellular matrix macromolecules and collagenase expression of two strains of progeria skin-derived cells. At low population doubling levels (PDL less than 10), confluent cultures of progeria fibroblasts made quiescent by lowering the concentration of serum in the medium did not respond to EGF while the mitotic activity of normal PDL-matched fibroblasts was almost maximally restored upon addition of EGF. No obvious difference between normal and low PDL progeria fibroblasts was observed in the number and in the affinity of the receptors measured by [125I]EGF binding. The synthesis of collagen and non-collagen proteins was similar in normal and affected cells at low and high serum concentration and both types of cells responded to EGF by a specific inhibition of collagen synthesis. Besides a normal level of mRNA coding for type I and type III collagens, collagenase and laminin, progeria fibroblasts expressed a high level of elastin and type IV collagen mRNA. Like normal fibroblasts, progeria cells responded to EGF by a decrease in the level of mRNA for fibrillar collagens and elastin. In contrast, a complete lack of response to EGF was observed for collagenase mRNA whereas the expression of this enzyme was strikingly induced by EGF in normal PDL-matched cells. The abnormal expression of type IV collagen was not significantly modified by EGF. At PDL greater than 10, progeria cells exhibited features of senescence. A significant reduction of collagen synthesis was observed and no further inhibition by EGF was recorded.

Topics: Cell Division; Cells, Cultured; Collagen; Elastin; Epidermal Growth Factor; Extracellular Matrix; Fibroblasts; Humans; Progeria; RNA, Messenger

Hutchinson-Gilford progeria is a unique, rare disease with markedly accelerated aging. The average lifespan of affected individuals is 12 years. Although the biochemical basis of the syndrome is unknown, its influence appears to be primarily upon mesodermal tissues. Characteristics such as the altered appearance of the skin and the extensive and fatal involvement of the cardiovascular system led us to study elastin production in cultured skin fibroblasts from three progeroid individuals. We found tropoelastin production by progeroid cells was elevated six- to nine-fold at the protein and mRNA levels, while relative collagen synthesis was similar to control strains. There was little difference between progeroid and normal cells in expression of total protein or in total cellular mRNA content. Western blot analysis of tropoelastin from progeroid fibroblasts confirmed increased production of elastin but revealed no gross changes in the molecular mass. The significant increase in tropoelastin expression lends support to the concept that progeria results from a mesenchymal dysplasia, and offers a possible biochemical marker for the phenotype.

Topics: Adolescent; Cells, Cultured; Child; Child, Preschool; Elastin; Female; Fibroblasts; Homeostasis; Humans; Male; Progeria; Reference Values; RNA, Messenger; Skin; Tropoelastin

Topics: Biopsy; Collagen; Elastin; Endoplasmic Reticulum; Fibroblasts; Humans; Microscopy, Electron; Mitochondria; Pigmentation Disorders; Progeria; Skin Diseases; Staining and Labeling