elastin and Pseudoxanthoma-Elasticum

Topics: Aged; Bronchiectasis; Collagen Diseases; Dermis; Dermoscopy; Diagnosis, Differential; Elastin; Female; Humans; Pseudoxanthoma Elasticum

Elastic fibers in the extracellular matrix are an integral component of dermal connective tissue. The resilience and elasticity required for normal structure and function of the skin may be attributed to the network of elastic tissue. Advances in our understanding of elastic tissue physiology provide a foundation for studying the pathogenesis of elastic tissue disorders. Many acquired disorders are nevertheless poorly understood due to the paucity of reported cases. Several acquired disorders in which accumulation or elastotic degeneration of dermal elastic fibers produces prominent clinical and histopathologic features have recently been described. They include elastoderma, linear focal elastosis, and late-onset focal dermal elastosis and must be differentiated from better-known disorders, among them acquired pseudoxanthoma elasticum, elastosis perforans serpiginosa, and Favré-Racouchot syndrome. Learning objective At the conclusion of this learning activity, participants should understand the similarities and differences between acquired disorders of elastic tissue that are characterized by an increase in elastic tissue, as well as the spectrum of solar elastotic dermatoses.

Topics: Connective Tissue Diseases; Diagnosis, Differential; Elastic Tissue; Elasticity; Elastin; Humans; Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a relatively rare heritable disorder affecting the skin, eyes and cardiovascular system, with considerable morbidity and mortality. The disease affects the elastic fibers of affected organs, which become progressively calcified. Thus, PXE has been considered as a prototypic heritable connective tissue disorder affecting the elastic fiber system. Recently, PXE has been linked to mutations in the MRP6/ABCC6 gene, a member of the ABC transporter family, expressed primarily in the liver and the kidneys. This information, together with clinical observations suggesting environmental, hormonal and/or dietary modulation of the disease, raises the intriguing possibility that PXE is a primary metabolic disorder at the environment-genome interface.

Topics: Age of Onset; ATP-Binding Cassette Transporters; Biological Transport, Active; Cardiovascular System; Elastin; Environmental Exposure; Eye; Female; Genetic Predisposition to Disease; Humans; Kidney; Liver; Male; Metabolism, Inborn Errors; Multidrug Resistance-Associated Proteins; Phenotype; Pseudoxanthoma Elasticum; Sex Factors; Skin

The elastic properties of many tissues such as the lung, dermis, and large blood vessels are due to the presence of elastic fibers in the extracellular space. These fibers have been shown by biochemical and ultrastructural analysis to be comprised of two distinct components, a more abundant amorphous component and the microfibrillar component. The microfibrillar component is found in 10- to 12-nm fibrils which are located primarily around the periphery of the amorphous component but, to some extent, interspersed within it. The protein, elastin, makes up the highly insoluble amorphous component and is responsible for the elastic properties. Elastin is found throughout the vertebrate kingdom except for very primitive fish and possesses an unusual chemical composition consonant with its characteristic physical properties. Elastin is composed largely of glycine, proline, and other hydrophobic residues and contains multiple lysine-derived cross-links, such as the desmosines, which link the individual polypeptide chains into a rubber-like network. The intervening, hydrophobic regions of the polypeptide chains between the cross-links are highly mobile, and the elastic properties of the fibers can be described in terms of the theory of rubber elasticity. Recent application of recombinant DNA techniques has led to further understanding of the structure of elastin. Analyses of the bovine and human elastin genes have demonstrated that the hydrophobic and cross-linking domains are encoded in separate exons. These exons tend to be small, varying from 27 to 114 base pairs, and are separated by large intervening sequences. Furthermore, DNA sequence analysis has demonstrated that the elastin molecule contains two cysteine residues which were not previously identified near the carboxy terminus and which may be important in the interaction of elastin with other extracellular matrix proteins. Further DNA sequencing should determine the complete amino acid sequence of elastin. Biosynthetic studies and in vitro translation of elastin mRNA have demonstrated that a 72,000-dalton polypeptide, designated tropoelastin, is the initial translation product. Analysis of several developing systems has demonstrated that elastin synthesis is controlled by the level of elastin mRNA. After packaging into membrane-bound vesicles in the Golgi apparatus, tropoelastin is secreted by exocytosis into the extracellular space where it is cross-linked by a copper-requiring extracellular enzyme, lys

Topics: Amino Acid Sequence; Amino Acids; Animals; Aorta; Base Sequence; Biological Evolution; Bone Diseases; Chemical Phenomena; Chemistry; Cutis Laxa; DNA; Elastin; Genes; Genetic Diseases, Inborn; Humans; Lung Diseases, Obstructive; Macromolecular Substances; Marfan Syndrome; Microscopy, Electron; Protein-Lysine 6-Oxidase; Pseudoxanthoma Elasticum; RNA, Messenger; Species Specificity; Syndrome; Tropoelastin; Vascular Diseases

This article reviews the diseases that may show epidermal perforation as a histologic feature. Many of these represent examples of transepithelial elimination (TEE), a mechanism by which the skin rids itself of abnormal substances. After a review of disorders in which perforation is an occasional finding, four diseases that have been considered essential perforating disorders are discussed: elastosis perforans serpiginosa (EPS), reactive perforating collagenosis (RPC), perforating folliculitis (PF), and Kyrle 's disease (KD). A review of the literature, including recent reports of perforating diseases associated with chronic renal failure, suggests that there may be considerable clinical and histologic overlap among PF, KD, and the adult form of "perforating collagenosis." A working classification for the perforating disorders is suggested.

Topics: Collagen Diseases; Elastic Tissue; Elastin; Folliculitis; Granuloma; Humans; Keratosis; Kidney Failure, Chronic; Microscopy, Electron; Pseudoxanthoma Elasticum; Skin; Skin Diseases

Topics: Animals; Arteries; Arteriosclerosis; Calcium; Collagen Diseases; Cricetinae; Elastic Tissue; Elastin; Humans; Lipid Metabolism; Lung; Microscopy, Electron; Models, Chemical; Molecular Conformation; Pancreatic Elastase; Pseudoxanthoma Elasticum; Pulmonary Emphysema; Skin Diseases; Tropoelastin

The elastic fibers present in various connective tissues of the body are responsible for physiologic elasticity of the organs. These fibers consist of 2 distinct components, elastin and the elastic fiber microfibrils. Controlled synthesis and balanced interaction of these 2 components are essential for normal fibrillogenesis. The intracellular biosynthesis of elastin by connective tissue cells, such as smooth muscle cells, involves assembly of the polypeptide chains on the membrane-bound ribosomes, hydroxylation of some prolyl residues to hydroxyproline, and secretion of the polypeptides packaged in Golgi vacuoles. In the extracellular space the elastin molecules assemble into fiber structures which are stabilized by the synthesis of complex covalent cross-links, desmosines. Recently, aberrations in the structure or metabolism of elastin have been detected in a variety of heritable and acquired diseases affecting skin and other connective tissues. These conditions include pseudoxanthoma elasticum, cutis laxa, and elastosis perforans serpiginosa, as well as arteriosclerosis and other degenerative changes of the vascular connective tissues.

Topics: Amino Acids; Arteriosclerosis; Chemical Phenomena; Chemistry; Collagen Diseases; Connective Tissue; Contractile Proteins; Cutis Laxa; Desmosine; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Female; Glycoproteins; Humans; Hydroxyproline; Marfan Syndrome; Menkes Kinky Hair Syndrome; Muscle Proteins; Pancreatic Elastase; Peptide Biosynthesis; Protein Precursors; Pseudoxanthoma Elasticum; X Chromosome

Topics: Animals; Arteriosclerosis; Chemical Phenomena; Chemistry; Chick Embryo; Copper; Deficiency Diseases; Elastic Tissue; Elastin; Fibroma; Guinea Pigs; Haplorhini; Histocytochemistry; Microscopy; Microscopy, Electron; Pseudoxanthoma Elasticum; Rats; Skin Neoplasms; Staining and Labeling; Swine

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

Pseudoxanthoma elasticum (PXE (OMIM 264800)) is an autosomal recessive connective tissue disorder mainly caused by mutations in the ABCC6 gene. PXE results in ectopic calcification primarily in the skin, eye and blood vessels that can lead to blindness, peripheral arterial disease and stroke. Previous studies found correlation between macroscopic skin involvement and severe ophthalmological and cardiovascular complications. This study aimed to investigate correlation between skin calcification and systemic involvement in PXE. Ex vivo nonlinear microscopy (NLM) imaging was performed on formalin fixed, deparaffinized, unstained skin sections to assess the extent of skin calcification. The area affected by calcification (CA) in the dermis and density of calcification (CD) was calculated. From CA and CD, calcification score (CS) was determined. The number of affected typical and nontypical skin sites were counted. Phenodex + scores were determined. The relationship between the ophthalmological, cerebro- and cardiovascular and other systemic complications and CA, CD and CS, respectively, and skin involvement were analyzed. Regression models were built for adjustment to age and sex. We found significant correlation of CA with the number of affected typical skin sites (r = 0.48), the Phenodex + score (r = 0.435), extent of vessel involvement (V-score) (r = 0.434) and disease duration (r = 0.48). CD correlated significantly with V-score (r = 0.539). CA was significantly higher in patients with more severe eye (p = 0.04) and vascular (p = 0.005) complications. We found significantly higher CD in patients with higher V-score (p = 0.018), and with internal carotid artery hypoplasia (p = 0.045). Significant correlation was found between higher CA and the presence of macula atrophy (β = - 0.44, p = 0.032) and acneiform skin changes (β = 0.40, p = 0.047). Based on our results, the assessment of skin calcification pattern with nonlinear microscopy in PXE may be useful for clinicians to identify PXE patients who develop severe systemic complications.

Topics: Adult; Aged; Calcification, Physiologic; Connective Tissue; Elastin; Female; Humans; Male; Middle Aged; Mutation; Pseudoxanthoma Elasticum; Retrospective Studies; Skin

Generalized arterial calcification of infancy (GACI) and pseudoxanthoma elasticum (PXE) are characterized by pathologic calcifications in the media of large- and medium sized arteries. GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. Different treatment approaches including bisphosphonates and orally administered pyrophosphate (PP

Topics: Animals; Antibodies; Aorta; Calcium Chelating Agents; Cell Line; Drug Carriers; Drug Compounding; Elastin; Female; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Multidrug Resistance-Associated Proteins; Nanoparticles; Pentetic Acid; Pseudoxanthoma Elasticum; Serum Albumin, Human; Vascular Calcification

Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up.

Topics: Case-Control Studies; Collagen; Connective Tissue; Elastin; Female; Humans; Image Processing, Computer-Assisted; Male; Nonlinear Optical Microscopy; Pseudoxanthoma Elasticum; Skin

Multiphoton microscopy (MPM) is a novel imaging technology that has recently become applicable for diagnostic purposes. The use of (near) infrared light in MPM allows for deep tissue imaging. In addition, this modality exploits the autofluorescent nature of extracellular matrix fibres within the skin.. To quantitate the structure and abundance of elastic fibres in human dermis in three dimensions utilizing autofluorescent signals generated by MPM for the objective examination of elastin-related skin disorders.. Cross-sections of skin samples from elastin-related disorders were analysed by MPM and correlated to histopathology. In situ visualization of elastic fibres by MPM was conducted by en face imaging of ex vivo skin samples through the intact epidermis. Image analysis software was used to quantify elastic fibres in three dimensions.. Based on the MPM-detected elastin-specific autofluorescence, we developed the Dermal Elastin Morphology Index (DEMI), calculated as the ratio of elastic fibre surface area and volume. This enabled objective three-dimensional quantification of elastic fibres. Quantitative scoring of sun-damaged skin using DEMI correlated with qualitative histopathological grading of the severity of solar elastosis. Furthermore, this approach was applied to changes in elastic fibre architecture in other disorders, such as pseudoxanthoma elasticum (PXE), PXE-like syndrome, elastofibroma, focal dermal elastosis, anetoderma, mid-dermal elastolysis and striae distensae. We imaged elastic fibres in intact ex vivo skin imaged en face through the epidermis, indicating that this approach could be used in vivo.. MPM has the potential for noninvasive in vivo visualization of elastic fibres in the dermis with near histological resolution. DEMI allows objective assessment of elastic fibres to support diagnosis and monitoring of disease progress or therapy of elastin-related skin disorders.

Topics: Adult; Aged; Aged, 80 and over; Elastin; Humans; Imaging, Three-Dimensional; Microscopy, Fluorescence, Multiphoton; Middle Aged; Pseudoxanthoma Elasticum; Skin Diseases

A number of beta-thalassemia (β-thal) patients in the course of the disease exhibit ectopic calcification affecting skin, eyes and the cardiovascular system. Clinical and histopathological features have been described similar to those in pseudoxanthoma elasticum (PXE), although different genes are affected in the two diseases. Cultured dermal fibroblasts from β-thal patients with and without PXE-like clinical manifestations have been compared for parameters of redox balance and for the expression of proteins, which have been already associated with the pathologic mineralisation of soft connective tissues. Even though oxidative stress is a well-known condition of β-thal patients, our results indicate that the occurrence of mineralized elastin is associated with a more pronounced redox disequilibrium, as demonstrated by the intracellular increase of anion superoxide and of oxidized proteins and lipids. Moreover, fibroblasts from β-thal PXE-like patients are characterized by decreased availability of carboxylated matrix Gla protein (MGP), as well as by altered expression of proteins involved in the vitamin K-dependent carboxylation process. Results demonstrate that elastic fibre calcification is promoted when redox balance threshold levels are exceeded and the vitamin K-dependent carboxylation process is affected decreasing the activity of MGP, a well-known inhibitor of ectopic calcification. Furthermore, independently from the primary gene defect, these pathways are similarly involved in fibroblasts from PXE and from β-thal PXE-like patients as well as in other diseases leading to ectopic calcification, thus suggesting that can be used as markers of pathologic mineralisation.

Topics: Adult; Advanced Oxidation Protein Products; beta-Thalassemia; Blotting, Western; Calcinosis; Calcium-Binding Proteins; Carboxylic Acids; Dermis; DNA Methylation; Elastic Tissue; Elastin; Extracellular Matrix Proteins; Female; Fibroblasts; Flow Cytometry; Glutathione Peroxidase; Glutathione Transferase; Humans; Lipid Peroxides; Male; Malondialdehyde; Matrix Gla Protein; Oxidative Stress; Pseudoxanthoma Elasticum; Superoxide Dismutase; Vitamin K

Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by mineralization of connective tissue, which leads to pathology in eye, skin and blood vessels. The disease is caused by mutations in ABCC6. To learn more about PXE eye pathology, we analyzed Bruch's membrane (BM) of the eye of an Abcc6 knockout mouse. With age, BM differences between Abcc6-/- and wild type mice became apparent. At two years of age, von Kossa staining indicated clear calcification of BM in Abcc6-/- mice, and not in healthy controls. Electron microscopy revealed BM changes as early as at 10 months of age: Fibrous structures with abnormal high electron-density were present in the central layers of BM of Abcc6-/- mice. EDX (Energy Dispersive X-ray) analysis demonstrated that these structures contained elevated levels of Ca, P and O. Since some of these electron-dense structures showed a banding pattern with periodicity of about 50 nm, they most likely represent calcified collagen fibers. Immunoelectron microscopy showed that the calcified structures were positive for collagen III. Remarkably, the elastic layer of BM appeared to have a normal ultrastructure, even in 2.5 year old Abcc6-/- mice. Our results suggest that Abcc6 deficiency in the mouse causes calcification of BM. While PXE is considered to affect primarily the elastic fibers, we found predominantly mineralization of collagen fibers.

Topics: Animals; ATP-Binding Cassette Transporters; Bruch Membrane; Calcinosis; Collagen Type III; Disease Models, Animal; Elastin; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Immunoelectron; Multidrug Resistance-Associated Proteins; Pseudoxanthoma Elasticum; Spectrometry, X-Ray Emission

Pseudoxanthoma elasticum (PXE) is a heritable disorder mainly characterized by calcified elastic fibers in cutaneous, ocular, and vascular tissues. PXE is caused by mutations in ABCC6, a gene encoding an ABC transporter predominantly expressed in liver and kidneys. The functional relationship between ABCC6 and elastic fiber calcification is unknown. We speculated that ABCC6 deficiency in PXE patients induces a persistent imbalance in circulating metabolite(s), which may impair the synthetic abilities of normal elastoblasts or specifically alter elastic fiber assembly. Therefore, we compared the deposition of elastic fiber proteins in cultures of fibroblasts derived from PXE and unaffected individuals. PXE fibroblasts cultured with normal human serum expressed and deposited increased amounts of proteins, but structurally normal elastic fibers. Interestingly, normal and PXE fibroblasts as well as normal smooth muscle cells deposited abnormal aggregates of elastic fibers when maintained in the presence of serum from PXE patients. The expression of tropoelastin and other elastic fiber-associated genes was not significantly modulated by the presence of PXE serum. These results indicated that certain metabolites present in PXE sera interfered with the normal assembly of elastic fibers in vitro and suggested that PXE is a primary metabolic disorder with secondary connective tissue manifestations.

Topics: Blood Proteins; Cardiovascular System; Cells, Cultured; Child; Connective Tissue; Elastic Tissue; Elastin; Eye; Female; Fibroblasts; Gene Expression Regulation; Humans; Male; Metabolic Diseases; Multidrug Resistance-Associated Proteins; Muscle, Smooth; Mutation; Pseudoxanthoma Elasticum; Skin; Tropoelastin

A method is described that could be of potential use for the rapid ultrastructural identification of abnormal and fragmented elastic fibers in very small wet samples of dermal biopsies from patients affected by Pseudoxanthoma elasticum (PXE). Moreover, the method, which consists of the use of sealed capsules transparent to electrons, allows the rapid and accurate localization and detection of mineralized areas in PXE patients and of their ion composition by X-ray microanalysis. This methodology could be of great help in any tissue disorder, especially in connective tissue disorders, characterized by structural alterations associated with ion precipitation.

Topics: Biopsy; Calcinosis; Connective Tissue Diseases; Elastic Tissue; Elastin; Electron Probe Microanalysis; Humans; Ions; Pseudoxanthoma Elasticum; Skin

Skin biopsies in patients with pseudoxanthoma elasticum (PXE) show elastic fiber fragmentation and calcium and proteoglycans accumulation. Assuming such changes to be present in the artery wall as well, we studied the influence of such alterations on function and structure of the human common carotid artery (CCA). Indeed, elastin fragmentation and increased calcium and proteoglycans content were present in the arteries of the two PXE patients examined. Internal diameter, distension and intima-media thickness (IMT) in the CCA of PXE patients (n = 19) and controls (n = 39) were determined by ultrasound (US). Pulse pressure was assessed in the brachial artery. The distensibility and compliance coefficients as well as the Young's modulus were calculated. Diameter and pulse pressure were not significantly different in PXE patients and controls. The distensibility and compliance coefficients were significantly greater in older PXE patients than in older controls. The distensibility coefficient decreased with age in both PXE patients and in controls. Unlike in controls, the compliance coefficient did not decrease and the Young's modulus barely increased with age in PXE patients. IMT was significantly greater at both younger and older ages and the Young's modulus was significantly smaller at older ages in PXE patients than in controls. The carotid artery is thicker and more elastic in PXE patients than in control subjects; differences are most pronounced at older ages. These alterations might be explained by the elastin fragmentation and proteoglycans accumulation as observed in these patients.

Topics: Aged; Aged, 80 and over; Aorta; Calcium; Carotid Artery, Common; Case-Control Studies; Elasticity; Elastin; Female; Humans; Male; Middle Aged; Proteoglycans; Pseudoxanthoma Elasticum; Ultrasonography

Topics: Connective Tissue Diseases; Cutis Laxa; Dermis; Elastic Tissue; Elastin; Humans; Multidrug Resistance-Associated Proteins; Mutation; Pseudoxanthoma Elasticum; Williams Syndrome

Late-onset focal dermal elastosis has recently been described as new clinical entity characterized by pseudoxanthoma elasticum-like eruptions and an accumulation of normal-appearing elastic fibres in the dermis. Elastin and collagen contents of the skin of 2 patients were 2- and 1.4-fold higher than in the skin of controls, respectively. A focal accumulation of elastin but not of fibrillin-1 was observed by immunohistochemical staining. The levels of type I and III collagen and elastin mRNAs isolated from cultured patient fibroblasts were elevated 2-3-fold compared with control fibroblasts. There was no significant change in the excretion of elastin peptides in the urine of patients and controls. These results suggest that the focal accumulation of elastic fibres in the patient skin may be related to overexpression of elastin rather than to altered degradation of elastin.

Topics: Age of Onset; Aged; Aged, 80 and over; Blotting, Northern; Collagen; Dermis; Elastic Tissue; Elastin; Female; Humans; Immunohistochemistry; Male; Middle Aged; Pseudoxanthoma Elasticum; RNA, Messenger; Skin

We report four patients with pseudoxanthoma elasticum-like papillary dermal elastolysis (PDE). Multiple small papules on the neck, clinically resembling pseudoxanthoma elasticum, and loss of the elastic fibre network in the papillary dermis were found in each case. Immunohistochemical staining for elastin and fibrillin-1 in one patient demonstrated the disappearance of elastin and fibrillin-1 in the papillary dermis. Site-matched normal skins of the elderly showed intact elastin but a lack of fibrillin-1 in the papillary dermis. The younger normal skins revealed intact elastin and fibrillin-1. The results suggest that fibrillin-1 is absent from the papillary dermis of the normal-appearing neck skin of the elderly and that the primary defect in PDE may be in elastin rather than in fibrillin-1.

Topics: Adult; Aged; Aged, 80 and over; Connective Tissue Diseases; Elastic Tissue; Elastin; Extracellular Matrix Proteins; Female; Fibrillin-1; Fibrillins; Humans; Microfilament Proteins; Middle Aged; Pseudoxanthoma Elasticum; Skin

Proteoglycans (PGs) were investigated in fibroblast cultures from both apparently normal and involved areas of skin from two patients affected with Pseudoxanthoma elasticum (PXE) and compared to control normal cells. Biochemical analysis showed that cells from the PXE-affected patients produced a PG population with stronger polyanion properties, as well as a markedly increased amount of high hydrodynamic-size PGs. Moreover, PGs from PXE-affected cells showed abnormal hydrophobic interaction properties when examined under associative conditions and included heparan sulphate (HS)-containing populations with anomalous electrophoretic mobility. These phenomena were particularly evident in the case of PGs secreted into the growth medium. In agreement with these findings immunohistochemical study showed alterations affecting decorin and biglycan, as well as a different content and distribution of HS-PGs in PXE-affected cells. The same biochemical and morphological alterations were confirmed for both patients on different cell cultures and were present in cells from both apparently normal and affected skin areas, being more pronounced in the latter. Our results indicate that PXE-affected fibroblasts in culture exhibit an abnormal PG metabolism, which could affect the normal assembly of extracellular matrix.

Topics: Adult; Cells, Cultured; Chromatography, Ion Exchange; DEAE-Cellulose; Elastin; Electrophoresis, Polyacrylamide Gel; Extracellular Matrix; Female; Fibroblasts; Fluorescent Antibody Technique; Humans; Middle Aged; Minerals; Proteoglycans; Pseudoxanthoma Elasticum; Skin

Pseudoxanthoma elasticum (PXE) is a rare heritable connective tissue disorder manifested by skin, ocular, and cardiovascular anomalies. The basic defect is unknown; however, the microscopic findings are indicative of defects in elastic fibers. Among the components of the elastic fibers are elastin and elastin-associated microfibrils.. We assessed the fidelity of this fibrillar system in PXE with the use of antibodies to fibrillin, a major component of elastin-associated microfibrils.. Using a well-established immunofluorescence assay, we studied fibrillin deposition in dermal fibroblast cultures from 16 patients with PXE.. Six of the 16 patients (37%) showed some abnormality of fibrillin deposition in fibroblasts derived from lesional skin. Fibroblasts from nonlesional skin displayed normal fibrillin immunofluorescence. The only sibship studied, however, was discordant for fibrillin immunostaining.. Unlike the findings in Marfan syndrome, these data are not suggestive of causal fibrillin defects in PXE.

Topics: Actin Cytoskeleton; Adult; Aged; Blotting, Northern; Cells, Cultured; Elastin; Extracellular Matrix Proteins; Female; Fibrillins; Fibroblasts; Fluorescent Antibody Technique; Humans; Male; Microfilament Proteins; Middle Aged; Pseudoxanthoma Elasticum; Skin

Pseudoxanthoma elasticum (PXE) is a connective tissue inherited disease characterized by dermal alterations and mineralization of the elastin fibres. To investigate its pathogenesis, which is still unknown, antibodies against the principal connective tissue components were assayed on ultrathin sections of dermis from 7 PXE subjects and 5 age matched controls. Both control and PXE elastin fibres were positive for heparan, dermatan and chondroitin 0-sulphates, decorin and biglycan. In PXE, elastin fibres were also highly positive for chondroitin 6-sulphate, vitronectin, fibronectin and serum amyloid antigen. Vitronectin and fibronectin were mostly concentrated in the areas of dense mineralization within the elastin fibres. The abnormal microfilament aggregates, often seen in PXE dermis, were positive for all the above mentioned molecular species as well as for collagen types I and III and fibrillin; on the contrary, they were always negative for elastin. The results suggest that PXE is a complex disorder, in which the whole extracellular matrix is deeply disturbed. Therefore, without excluding an elastin gene defect, the data seem rather to suggest that PXE is a disorder of the mechanisms controlling the production of matrix constituents and that elastin mineralization is caused by molecules abnormally produced and entrapped within the fibre during elastin fibrogenesis.

Topics: Actin Cytoskeleton; Adult; Collagen; Elastin; Extracellular Matrix; Glycoproteins; Humans; Immunohistochemistry; Male; Microscopy, Immunoelectron; Microtomy; Pseudoxanthoma Elasticum; Skin; Vitronectin

An intragenic elastin Hinf I polymorphism has been used to study the inheritance of elastin alleles in a family considered to show recessive inheritance of pseudoxanthoma elasticum (PXE). The marker has proved informative, excluding the elastin gene as a cause of PXE in this family. In addition, whole genomic human elastin clones were used in Southern analysis to screen the family for gross elastin gene rearrangements, but none were detected.

Topics: Adolescent; Alleles; Elastin; Family; Female; Genetic Markers; Humans; Mutation; Pedigree; Polymorphism, Genetic; Pseudoxanthoma Elasticum

Two cases of pseudoxanthoma elasticum (PXE) were reported. Biochemical studies of collagen, glycosaminoglycan, and elastin content were performed using skin specimens from affected lesions. Hydroxyproline content was reduced approximately 46% and 24% in cases 1 and 2, respectively. The reduction in collagen content resulted from the reduction in the lower dermis, not from that in the upper dermis. Glycosaminoglycan content in PXE was also decreased, with a slight increase in the ratio of hyaluronic acid to dermatan sulfate. Isodesmosine content in PXE was increased 3.2- and 2.2-fold in cases 1 and 2, respectively. These results suggest that the major and primary biochemical changes in PXE are an increase in elastin content.

Topics: Adult; Collagen; Elastin; Extracellular Matrix; Female; Glycosaminoglycans; Humans; Hydroxyproline; Middle Aged; Pseudoxanthoma Elasticum; Skin

Pseudoxanthoma elasticum (PXE) is a disorder of connective tissue in which abnormalities of elastic tissue and collagen are found. The purpose of this study was to examine the ultrastructure and distribution of connective tissue components in lesional and non-lesional skin of patients by means of indirect immunofluorescence, electron microscopy and indirect immunoelectron microscopy. Prominent abnormalities of elastic tissue were seen on electron microscopy and confirmed by immunoelectron microscopy. Abnormal elastic fibers containing electron-dense bodies and holes were seen even in non-lesional skin. In addition, the normal pattern of collagen bundles was disrupted in lesional skin, but not in non-lesional skin of patients with PXE. The majority of individual collagen fibrils appeared normal by electron microscopy. The distribution of type IV collagen and laminin was normal in small blood vessels. Finally, abnormalities in the distribution of fibronectin were seen. The finding of atypical elastic fibers in non-lesional skin supports an early role for elastic tissue components in the pathogenesis of PXE. Interactions between elastin, collagen and other matrix substances may explain some of the abnormalities seen.

Topics: Collagen; Connective Tissue; Elastin; Fibronectins; Humans; Microscopy, Electron; Microscopy, Immunoelectron; Procollagen; Pseudoxanthoma Elasticum

Topics: Blood Vessels; Bruch Membrane; Calcinosis; Elastin; Fibrillins; Genes, Recessive; Humans; Microfilament Proteins; Microscopy, Electron; Mutation; Pseudoxanthoma Elasticum; Skin

The interference of penicillamine with collagen and elastin cross-linking can lead to wrinkling and anetoderma-like lesions in flexural areas as well as fragility and hemorrhagic blisters in pressure areas. These changes are seen primarily in patients with Wilson's disease or cystinuria who are on long-term therapy. This is a report of a patient with cystinuria on long-term, high-dose penicillamine who developed pseudoxanthoma-elasticum-like lesions. Coalescent yellow papules with a 'plucked-chicken skin' appearance were seen in the axillae and on the neck while redundant skin folds were noted in the anterior axillary line and lower buttocks. By light and electron microscopy, involved and uninvolved skin demonstrated 'lumpy-bumpy' dermal elastic fibers with no calcium deposition. These histologic changes are similar to those previously described in patients with penicillamine-induced skin lesions.

Topics: Aged; Collagen; Elastin; Humans; Male; Microscopy, Electron; Penicillamine; Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a heritable disorder of connective tissue that is characterized by redundant folds of skin in flexural areas. There is considerable evidence that suggests that the elastic fiber is the main site of the abnormality although the primary molecular defect has not been identified. The aim of this study was to identify differences between PXE and normal skin elastins. Elastins from normal, nonsolar-exposed skin, and pseudoxanthoma elasticum lesional skin were purified and their solubilization by pancreatic elastase was compared. Results demonstrated that elastin derived from normal skin was more susceptible to proteolytic cleavage than elastin purified from either pseudoxanthoma elasticum lesional skin or ligamentum nuchae. Pretreatment of the lesional elastin with testicular hyaluronidase increased its solubilization two-fold and generated a unique 15,000 Da molecular weight fragment. Elastin prepared from PXE skin may contain bound glycosaminoglycans which interfere with elastase activity. The susceptibility of normal skin elastin to proteolytic degradation may have implications in the study of aging skin.

Topics: Adult; Elastin; Electrophoresis, Polyacrylamide Gel; Humans; Hyaluronoglucosaminidase; Pancreatic Elastase; Pseudoxanthoma Elasticum; Skin

Abnormalities in the amount of skin elastin occur in several cutaneous disorders. The number of elastic fibers is increased in elastotic disorders such as pseudoxanthoma elasticum (PXE) and cutis rhomboidalis nuchae (actinic elastosis, AE) and is decreased in elastolytic disorders such as cutis laxa (CL). We describe a procedure to quantify desmosines and elastin in small amounts of skin using high-performance liquid chromatography (HPLC). Biopsies were obtained from normal, nonsolar exposed skin and from the lesional skin of patients with PXE, cutis rhomboidalis nuchae, and CL. Specimens were subjected to hot alkali treatment and the desmosines were released by acid hydrolysis and quantified by HPLC. The mean value for normal skin was 252 +/- 28 ng desmosines per milligram wet weight (SD, n = 5). The disorders of elastosis (PXE and AE) demonstrated a two- to fivefold increased content of desmosines. In contrast, the elastolytic disorder (CL) had only 20% of the normal content of desmosines. Furthermore, PXE and normal skin elastins had the same amount of desmosines per milligram purified elastin. This method could be used to evaluate the extent of elastosis or elastolysis in a particular lesion.

Topics: Adult; Aged; Amino Acids; Chromatography, High Pressure Liquid; Cutis Laxa; Desmosine; Elastin; Humans; Isodesmosine; Middle Aged; Pseudoxanthoma Elasticum; Skin; Skin Diseases

Histologic paraffin sections of pseudoxanthoma elasticum (PXE)-involved skin of forearm and axilla were used for histochemistry and immunohistochemical and analytical electron microscopy to study the progressive mineralization in the dermis of patients with PXE. The von Kossa technique identified mineral deposits throughout the reticular PXE dermis. X-ray analysis revealed patterns of calcium and phosphorus deposition in the von Kossa-positive areas, and the immunohistochemical staining using monoclonal antibodies identified increased chondroitin-6-sulfate in these areas when compared with normal skin. Scanning transmission electron microscopy observation combined with X-ray dot mapping show calcium and phosphorus to be codistributed within the mineralized area. This study confirms by new methods the increase in chondroitin-6-sulfate, alterations in elastin and collagen, and a high calcium and phosphorus elemental distribution matching the mineralized area in the PXE dermis.

Topics: Calcium; Collagen; Contractile Proteins; Elastic Tissue; Elastin; Electron Probe Microanalysis; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Immunohistochemistry; Microscopy, Electron; Minerals; Phosphorus; Proteoglycans; Pseudoxanthoma Elasticum; RNA Splicing Factors; Skin

Topics: Cations, Divalent; Cells, Cultured; Cutis Laxa; Elastin; Fibroblasts; Humans; Keratosis; Oligopeptides; Pancreatic Elastase; Pseudoxanthoma Elasticum; Skin

Pseudoxanthoma elasticum is a genetic disease characterized by progressive mineralization of elastic fibers. Previous studies suggested that other components, apart from elastin, might be involved in the alterations of this connective tissue disorder (Martinez-Hernandez and Huffer, 1974; Pasquali Ronchetti et al., 1981; 1986). Evidence is presented that proteoglycan metabolism is altered in PXE-affected patient. Urinary GAGs suggests an increased degradation of glucosamine-containing GAGs in the patient. Pulse and chase experiments on in vitro skin fibroblasts indicated a decreased rate of synthesis of [35SO4] containing GAGs or an increase of their turnover rate in PXE. Moreover, when PGs produced from skin fibroblasts were identified by ultracentrifugation and gel filtration in associative conditions, PXE fibroblasts produced a significantly higher amount of the high molecular weight fraction of sulfated PGs. This high molecular weight material was present both in the medium and in the matrix and disappeared under dissociative conditions or after treatment with hyaluronidase or with pancreas elastase. By electron microscopy, PXE fibroblasts appeared to produce and secrete an enormous amount of toluidine blue 0 positive material organized as filaments and amorphous masses. These data are in agreement with previous observations of the presence of abnormal masses of microfilaments, in the dermis of PXE patients, which were sensitive to hyaluronidase and partially to trypsin and elastase (Pasquali Ronchetti et al., 1986). The results seem to confirm that at least some of the alterations of connective tissues in PXE are due to abnormal PGs metabolism and to their tendency to form abnormal aggregates in the extracellular space.

Topics: Adult; Biopsy; Cells, Cultured; Elastin; Female; Fibroblasts; Glycosaminoglycans; Humans; Hyaluronoglucosaminidase; Microscopy, Electron; Pancreatic Elastase; Proteoglycans; Pseudoxanthoma Elasticum; Skin

A patient with cystinuria who was treated with large doses of D-penicillamine for 19 years developed skin abnormalities resembling those seen in pseudoxanthoma elasticum. Biochemical and histological examination of the dermis showed that the collagen content, the ratio of the major genetic forms of collagen and the distribution of collagen types was normal. Light microscopy demonstrated the presence of vastly increased amounts of elastin in the dermis, and the individual elastin fibres were shown by electron microscopy to be abnormal; chemical analysis showed the elastin to be poorly cross-linked. Some of the collagen also appeared structurally abnormal, and biochemically resembled that seen in the dermis of a young child with respect to cross-linking and hexosyl-lysine content. The therapy led to an increased deposition of collagen and elastin fibres which appeared abnormal, and resulted in an increase in total skin surface area. These data indicate that D-penicillamine was not fully effective in inhibiting collagen and elastin cross-linking, and appeared to prevent or inhibit the natural maturation process of the collagen.

Topics: Aged; Collagen; Elastin; Female; Humans; Male; Middle Aged; Penicillamine; Pseudoxanthoma Elasticum; Skin

Topics: Axilla; Elastin; Humans; Male; Microscopy, Electron; Middle Aged; Penicillamine; Pseudoxanthoma Elasticum; Skin

The elastic fibers in the skin and other organs can be affected in several disease processes. In this study, we have developed morphometric techniques that allow accurate quantitation of the elastic fibers in punch biopsy specimens of skin. In this procedure, the elastic fibers, visualized by elastin-specific stains, are examined through a camera unit attached to the microscope. The black and white images sensing various gray levels are then converted to binary images after selecting a threshold with an analog threshold selection device. The binary images are digitized and the data analyzed by a computer program designed to express the properties of the image, thus allowing determination of the volume fraction occupied by the elastic fibers. As an independent measure of the elastic fibers, alternate tissue sections were used for assay of desmosine, an elastin-specific cross-link compound, by a radioimmunoassay. The clinical applicability of the computerized morphometric analyses was tested by examining the elastic fibers in the skin of five patients with pseudoxanthoma elasticum or Buschke-Ollendorff syndrome. In the skin of 10 healthy control subjects, the elastic fibers occupied 2.1 +/- 1.1% (mean +/- SD) of the dermis. The volume fractions occupied by the elastic fibers in the lesions of pseudoxanthoma elasticum or Buschke-Ollendorff syndrome were increased as much as 6-fold, whereas the values in the unaffected areas of the skin in the same patients were within normal limits. A significant correlation between the volume fraction of elastic fibers, determined by computerized morphometric analyses, and the concentration of desmosine, quantitated by radioimmunoassay, was noted in the total material. These results demonstrate that computerized morphometric techniques are helpful in characterizing disease processes affecting skin. This methodology should also be applicable to other tissues that contain elastic fibers and that are affected in various heritable and acquired diseases.

Topics: Amino Acids; Desmosine; Diagnosis, Computer-Assisted; Elastic Tissue; Elastin; Histological Techniques; Humans; Pseudoxanthoma Elasticum; Radioimmunoassay; Skin

Previous morphologic observations have suggested abnormalities in the elastic fibers in a number of both inherited and acquired diseases. Recent progress made in understanding of the normal biology of elastin has allowed us to examine these diseases by biochemical means. In this review we are discussing the current status of the research on the elastin diseases with particular emphasis on clinical conditions affecting skin, as for example, cutis laxa, pseudoxanthoma elasticum, and the Buschke-Ollendorff syndrome. In addition, we present new data which appears to be the first demonstration of an elastin abnormality in the Marfan syndrome.

Topics: Connective Tissue Diseases; Cutis Laxa; Elastin; Humans; Marfan Syndrome; Menkes Kinky Hair Syndrome; Pseudoxanthoma Elasticum; Skin; Skin Diseases

Angioid streaks were observed in 21 of 242 patients with homozygous sickle cell disease. Two morphological types were observed. There is no evidence that angioid streaks in Jamaican patients are related to pseudoxanthoma elasticum.

Topics: Adult; Anemia, Sickle Cell; Angioid Streaks; Elastin; Female; Fluorescein Angiography; Humans; Jamaica; Male; Middle Aged; Pseudoxanthoma Elasticum; Skin

Ultrastructural and biochemical studies of the dermis from patients with pseudoxanthoma elasticum are described. Elastin fibers showed mineral deposits that were associated with an elastin material exhibiting altered affinity for the electron microscopical stains and altered ultrastructural organization. In the most affected patient the elastin was shown to be increased and to have an abnormal amino acid composition. In some patients the collagen fibers were laterally fused. The ground substance was increased as evidenced by electron microscopy and confirmed by a slight increase in uronic acids, hexosamines, and neutral sugars.

Topics: Amino Acids; Collagen; Elastin; Female; Humans; Male; Proteoglycans; Pseudoxanthoma Elasticum; Skin

Topics: Connective Tissue Diseases; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Humans; Pseudoxanthoma Elasticum

Examination by electron microscopy of the elastic fibers of individuals with Pseudoxanthoma Elasticum (PXE) revealed that the principal alterations were in the elastin moiety of the elastic fibers. The elastin had a granular appearance, an increased affinity for cationic stains, and it often demonstrated sites of increased density presumed to represent foci of calcification. In contrast to the elastin, the microfibrillar component of the elastic fibers was unchanged, both in morphologic appearance and in distribution. There was no clear correlation between the extent of the morphologic alteration in the elastic fiber and the level of clinical severity. Morphologically altered fibers were often found together with unaltered fibers. Changes similar to those seen in patients with PXE were also found in biopsies obtained from clinically unaffected consanguinous relatives. The pattern of inheritance in several of the families examined was compatible with autosomal recessive, whereas in at least one family a more complex mode of transmission seems likely. The electron microscopic data therefore provide further support for the genetic heterogeneity of PXE.

Topics: Adolescent; Adult; Aged; Collagen; Consanguinity; Elastic Tissue; Elastin; Female; Genes, Recessive; Heterozygote; Humans; Male; Middle Aged; Pedigree; Pseudoxanthoma Elasticum

Elastic fibers have been shown to contain two proteins, insoluble elastin and the elastic fiber microfibril, a glycoprotein. The microfibril has been suggested to play a morphogenetic role in determining the presumptive shape and direction of the forming elastic fiber. The principal alteration seen in individuals with the disease Pseudoxanthoma Elasticum is in insoluble elastin which loses its amorphous appearance and affinity for anionic stains, and takes on a finely granular appearance and shows increased affinity for cationic stains. Normal elastic fiber microfibrils are sometimes associated with this material; although, in general, these structures are not present in the elastic fibers that are markedly altered in this disease.

Topics: Animals; Cattle; Elastic Tissue; Elastin; Genes, Recessive; Humans; Ligaments; Microscopy, Electron; Morphogenesis; Neck; Pseudoxanthoma Elasticum; Rats; Tendons

Skin biopsy material obtained from 2 patients with pseudoxanthoma elasticum associated with congenital hyperphosphatasia was compared with skin biopsy material obtained from 3 patients with pseudoxanthoma elasticum unassociated with any other disease. Clinically normal skin showed calcification of normal-appearing elastin as the initial change in pseudoxanthoma elasticum. Elastin fibers become more ravelled as the disease progresses. A previously unreported early transient calcification of collagen was demonstrated. Other abnormal collagen forms may also be present. The Von Kossa stain appears to be the stain of choice for identifying these earliest histologic changes.

Topics: Adolescent; Adult; Biopsy; Calcinosis; Collagen; Elastin; Female; Humans; Middle Aged; Phosphoric Monoester Hydrolases; Pseudoxanthoma Elasticum; Skin

Topics: Angioid Streaks; Biopsy; Calcinosis; Calcium; Child; Elastin; Female; Histiocytes; Histocytochemistry; Humans; Male; Microscopy, Electron; Middle Aged; Phosphorus; Pseudoxanthoma Elasticum; Skin; Syndrome

Topics: Biopsy; Carbon Radioisotopes; Elastin; Glutamine; Humans; Hydroxyproline; Microbial Collagenase; Proline; Pseudoxanthoma Elasticum; Skin

Two cases of elastofibroma dorsi are reported and the light and electron microscopic features analysed. The appearances suggest that the characteristic fibres and globules that stain as for elastin arise by denaturation of collagen. The fibres differ from the elastin of arterial wall, elastotic degeneration of skin, and pseudoxanthoma elasticum. The morphology and clinical behaviour indicate that elastofibroma dorsi is a reactive fibromatosis rather than a true neoplasm.

Topics: Arteries; Back; Collagen; Elastic Tissue; Elastin; Female; Fibroma; Humans; Microscopy, Electron; Middle Aged; Pseudoxanthoma Elasticum; Scapula; Skin

Topics: Blood Chemical Analysis; Elastin; Endopeptidases; Humans; Pancreatic Elastase; Proteins; Pseudoxanthoma Elasticum

Topics: Elastin; Humans; Proteins; Pseudoxanthoma Elasticum; Skin; Skin Diseases