transforming-growth-factor-beta and Ehlers-Danlos-Syndrome

Recent progress in the study of hereditary large vessel diseases such as Marfan syndrome (MFS) have not only identified responsible genes but also provided better understanding of the pathophysiology and revealed possible new therapeutic targets. Genes identified for these diseases include FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, SKI, EFEMP2, COL3A1, FLNA, ACTA2, MYH11, MYLK and SLC2A10, as well as others. Their dysfunction disrupts the function of transforming growth factor-β (TGF-β) signaling pathways, as well as that of the extracellular matrix and smooth muscle contractile apparatus, resulting in progression of structural damage to large vessels, including aortic aneurysms and dissections. Notably, it has been shown that the TGF-β signaling pathway has a key role in the pathogenesis of MFS and related disorders, which may be important for development of strategies for medical and surgical treatment of thoracic aortic aneurysms and dissections.

Topics: Aortic Aneurysm, Thoracic; Aortic Dissection; Ehlers-Danlos Syndrome; Fibrillin-1; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mutation; Signal Transduction; Transforming Growth Factor beta

Thoracic aortic aneurysms (TAAs) are potentially devastating, and due to their asymptomatic behavior, pose a serious health risk characterized by the lack of medical treatment options and high rates of surgical morbidity and mortality. Independent of the inciting stimuli (biochemical/mechanical), TAA development proceeds by a multifactorial process influenced by both cellular and extracellular mechanisms, resulting in alterations of the structure and composition of the vascular extracellular matrix (ECM). While the role of enhanced ECM proteolysis in TAA formation remains undisputed, little attention has been focused on the upstream signaling events that drive the remodeling process. Recent evidence highlighting the dysregulation of transforming growth factor-beta (TGF-beta) signaling in ascending TAAs from Marfan syndrome patients has stimulated an interest in this intracellular signaling pathway. However, paradoxical discoveries have implicated both enhanced TGF-beta signaling and loss of function TGF-beta receptor mutations, in aneurysm formation; obfuscating a clear functional role for TGF-beta in aneurysm development. In an effort to elucidate this subject, TGF-beta signaling and its role in vascular remodeling and pathology will be reviewed, with the aim of identifying potential mechanisms of how TGF-beta signaling may contribute to the formation and progression of TAA.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Disease Progression; Ehlers-Danlos Syndrome; Extracellular Matrix; Genetic Predisposition to Disease; Humans; Marfan Syndrome; Mutation; Peptide Hydrolases; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

In contrast with adults, thoracic aortic aneurysms in children are usually associated with connective tissue defect syndromes. As such, there are phenotypic clues to identify patients at risk. Marfan syndrome, Loeys-Dietz syndrome, and bicuspid aortic valve syndrome account for the majority of these aneurysms. Indications for surgery as well as surgical options differ according to diagnosis and are reviewed herein.

Topics: Aortic Aneurysm, Thoracic; Aortic Valve; Blood Vessel Prosthesis Implantation; Child; Ehlers-Danlos Syndrome; Humans; Marfan Syndrome; Mutation; Phenotype; Syndrome; Transforming Growth Factor beta

Type V collagen is a regulatory fibrillar collagen essential for type I collagen fibril nucleation and organization and its deficiency leads to structurally abnormal extracellular matrix (ECM). Haploinsufficiency of the Col5a1 gene encoding α(1) chain of type V collagen is the primary cause of classic Ehlers-Danlos syndrome (EDS). The mechanisms by which this initial insult leads to the spectrum of clinical presentation are not fully understood. Using transcriptome analysis of skin and Achilles tendons from Col5a1 haploinsufficient (Col5a1+/-) mice, we recognized molecular alterations associated with the tissue phenotypes. We identified dysregulation of ECM components including thrombospondin-1, lysyl oxidase, and lumican in the skin of Col5a1+/- mice when compared with control. We also identified upregulation of transforming growth factor β1 (Tgf-β) in serum and increased expression of pSmad2 in skin from Col5a1+/- mice, suggesting Tgf-β dysregulation is a contributor to abnormal wound healing and atrophic scarring seen in classic EDS. Together, these findings support altered matrix to cell signaling as a component of the pathogenesis of the tissue phenotype in classic EDS and point out potential downstream signaling pathways that may be targeted for the treatment of this disease.

Topics: Animals; Collagen; Collagen Type V; Disease Models, Animal; Ehlers-Danlos Syndrome; Haploinsufficiency; Mice; Transforming Growth Factor beta

Preterm birth is the leading cause of newborn mortality in the United States and about one third of cases are caused by preterm premature rupture of fetal membranes, a complication that is frequently observed in patients with Ehlers-Danlos Syndrome. Notably, a subtype of Ehlers-Danlos Syndrome is caused by expression of abnormal biglycan and decorin proteoglycans. As compound deficiency of these two small leucine-rich proteoglycans is a model of preterm birth, we investigated the fetal membranes of Bgn(-/-); Dcn(-/-) double-null and single-null mice. Our results showed that biglycan signaling supported fetal membrane remodeling during early gestation in the absence of concomitant changes in TGFβ levels. In late gestation, biglycan signaling acted in a TGFβ-dependent manner to aid in membrane stabilization. In contrast, decorin signaling supported fetal membrane remodeling at early stages of gestation in a TGFβ-dependent manner, and fetal membrane stabilization at later stages of gestation without changes in TGFβ levels. Furthermore, exogenous soluble decorin was capable of rescuing the TGFβ signaling pathway in fetal membrane mesenchymal cells. Collectively, these findings provide novel targets for manipulation of fetal membrane extracellular matrix stability and could represent novel targets for research on preventive strategies for preterm premature rupture of fetal membranes.

Topics: Analysis of Variance; Animals; Biglycan; Blotting, Western; Cell Culture Techniques; Decorin; Disease Models, Animal; DNA Primers; Ehlers-Danlos Syndrome; Enzyme-Linked Immunosorbent Assay; Extraembryonic Membranes; Immunohistochemistry; Mice; Premature Birth; Signal Transduction; Transforming Growth Factor beta

Patients with congenital adrenal hyperplasia (CAH) with tenascin-X deficiency (CAH-X syndrome) have both endocrine imbalances and characteristic Ehlers Danlos syndrome phenotypes. Unlike other subtypes, tenascin-X-related Ehlers Danlos syndrome is caused by an extracellular matrix protein deficiency rather than a defect in fibrillar collagen or a collagen-modifying enzyme, and the understanding of the disease mechanisms is limited. We hypothesized that transforming growth factor-β pathway dysregulation may, in part, be responsible for connective tissue phenotypes observed in CAH-X, due to this pathway's known role in connective tissue disorders. Fibroblasts and direct tissue from human skin biopsies from CAH-X probands and age- and sex-matched controls were screened for transforming growth factor-β biomarkers known to be dysregulated in other hereditary disorders of connective tissue. In CAH-X fibroblast lines and dermal tissue, pSmad1/5/8 was significantly upregulated compared to controls, suggesting involvement of the bone morphogenetic protein pathway. Additionally, CAH-X samples compared to controls exhibited significant increases in fibroblast-secreted TGF-β3, a cytokine important in secondary palatal development, and in plasma TGF-β2, a cytokine involved in cardiac function and development, as well as palatogenesis. Finally, MMP-13, a matrix metalloproteinase important in secondary palate formation and tissue remodeling, had significantly increased mRNA and protein expression in CAH-X fibroblasts and direct tissue. Collectively, these results demonstrate that patients with CAH-X syndrome exhibit increased expression of several transforming growth factor-β biomarkers and provide a novel link between this signaling pathway and the connective tissue dysplasia phenotypes associated with tenascin-X deficiency.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Bone Morphogenetic Proteins; Child; Child, Preschool; Ehlers-Danlos Syndrome; Female; Fibroblasts; Gene Expression Regulation; Humans; Immunohistochemistry; Male; Matrix Metalloproteinase 13; Signal Transduction; Tenascin; Transforming Growth Factor beta; Transforming Growth Factor beta2; Transforming Growth Factor beta3; Young Adult

Vascular Ehlers-Danlos syndrome (VEDS) causes reduced life expectancy because of arterial dissections/rupture and hollow organ rupture. Although the causative gene, COL3A1, was identified >20 years ago, there has been limited progress in understanding the disease mechanisms or identifying treatments.. We studied inflammatory and transforming growth factor-β (TGF-β) signaling biomarkers in plasma and from dermal fibroblasts from patients with VEDS. Analyses were done in terms of clinical disease severity, genotype-phenotype correlations, and body composition and fat deposition alterations. VEDS subjects had increased circulating TGF-β1, TGF-β2, monocyte chemotactic protein-1, C-reactive protein, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and leptin and decreased interleukin-8 versus controls. VEDS dermal fibroblasts secreted more TGF-β2, whereas downstream canonical/noncanonical TGF-β signaling was not different. Patients with COL3A1 exon skipping mutations had higher plasma intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and VEDS probands had abnormally high plasma C-reactive protein versus affected patients identified through family members before any disease manifestations. Patients with VEDS had higher mean platelet volumes, suggesting increased platelet turnover because of ongoing vascular damage, as well as increased regional truncal adiposity.. These findings suggest that VEDS is a systemic disease with a major inflammatory component. C-reactive protein is linked to disease state and may be a disease activity marker. No changes in downstream TGF-β signaling and increased platelet turnover suggest that chronic vascular damage may partially explain increased plasma TGF-β1. Finally, we found a novel role for dysregulated TGF-β2, as well as adipocyte dysfunction, as demonstrated through reduced interleukin-8 and elevated leptin in VEDS.

Topics: Adipokines; Adolescent; Adult; Biomarkers; Body Composition; C-Reactive Protein; Child; Collagen Type III; Ehlers-Danlos Syndrome; Female; Fibroblasts; Genetic Association Studies; Humans; Inflammation; Male; Middle Aged; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Young Adult

Topics: Ehlers-Danlos Syndrome; Female; Humans; Inflammation; Male; Transforming Growth Factor beta

Ehlers-Danlos syndrome (EDS) is a heterogeneous connective tissue disorder involving skin and joint laxity and tissue fragility. A new type of EDS, similar to kyphoscoliosis type but without lysyl hydroxylase deficiency, has been investigated. We have identified a homozygous CHST14 (carbohydrate sulfotransferase 14) mutation in the two familial cases and compound heterozygous mutations in four sporadic cases. CHST14 encodes dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers active sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 4 of the N-acetyl-D-galactosamine (GalNAc) residues of dermatan sulfate (DS). Transfection experiments of mutants and enzyme assays using fibroblast lysates of patients showed the loss of D4ST1 activity. CHST14 mutations altered the glycosaminoglycan (GAG) components in patients' fibroblasts. Interestingly, DS of decorin proteoglycan, a key regulator of collagen fibril assembly, was completely lost and replaced by chondroitin sulfate (CS) in the patients' fibroblasts, leading to decreased flexibility of GAG chains. The loss of the decorin DS proteoglycan due to CHST14 mutations may preclude proper collagen bundle formation or maintenance of collagen bundles while the sizes and shapes of collagen fibrils are unchanged as observed in the patients' dermal tissues. These findings indicate the important role of decorin DS in the extracellular matrix and a novel pathomechanism in EDS.

Topics: Adult; Amino Acid Sequence; Carbohydrate Sulfotransferases; Child; Collagen; Decorin; Dermis; Ehlers-Danlos Syndrome; Extracellular Matrix Proteins; Female; Fibroblasts; Glycosaminoglycans; Humans; Male; Models, Biological; Molecular Sequence Data; Mutation; Pedigree; Proteoglycans; Signal Transduction; Sulfotransferases; Transforming Growth Factor beta

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Aneurysm, Ruptured; Aortic Dissection; Celiprolol; Ehlers-Danlos Syndrome; Humans; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown.. Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice.. Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

Topics: Adolescent; Amino Acid Sequence; Animals; Bone Morphogenetic Proteins; Cation Transport Proteins; Cells, Cultured; Connective Tissue; DNA Mutational Analysis; Ehlers-Danlos Syndrome; Humans; Mice; Mice, Knockout; Models, Biological; Molecular Sequence Data; Morphogenesis; Osteogenesis; Pedigree; Sequence Homology, Amino Acid; Signal Transduction; Transforming Growth Factor beta; Young Adult; Zinc

The metalloproteinase ADAMTS-2 has procollagen I N-proteinase activity capable of cleaving procollagens I and II N-propeptides in vitro, whereas mutations in the ADAMTS-2 gene in dermatosparaxis and Ehlers-Danlos syndrome VIIC show this enzyme to be responsible in vivo for most biosynthetic processing of procollagen I N-propeptides in skin. Yet despite its important role in the regulation of collagen deposition, information regarding regulation and substrate specificity of ADAMTS-2 has remained sparse. Here we demonstrate that ADAMTS-2 can, like the procollagen C-proteinases, be regulated by transforming growth factor-beta 1 (TGF-beta 1), with implications for mechanisms whereby this growth factor effects net increases in formation of extracellular matrix. TGF-beta 1 induced ADAMTS-2 mRNA approximately 8-fold in MG-63 osteosarcoma cells in a dose- and time-dependent, cycloheximide-inhibitable manner, which appeared to operate at the transcriptional level. Secreted ADAMTS-2 protein induced by TGF-beta 1 was 132 kDa and was identical in size to the fully processed, active form of the protease. Biosynthetic processing of ADAMTS-2 to yield the 132-kDa form is shown to be a two-step process involving sequential cleavage by furin-like convertases at two sites. Surprisingly, purified recombinant ADAMTS-2 is shown to cleave procollagen III N-propeptides as effectively as those of procollagens I and II, whereas processing of procollagen III is shown to be decreased in Ehlers-Danlos VIIC. Thus, the dogma that procollagen I and procollagen III N-proteinase activities are provided by separate enzymes appears to be false, whereas the phenotypes of dermatosparaxis and Ehlers-Danlos VIIC may arise from defects in both type I and type III collagen biosynthesis.

Topics: ADAM Proteins; ADAMTS Proteins; ADAMTS4 Protein; Amino Acid Sequence; Blotting, Western; Collagen; Collagen Type I; Ehlers-Danlos Syndrome; Electrophoresis, Polyacrylamide Gel; Fibroblasts; Gene Expression Regulation; Glycosylation; Humans; Keratinocytes; Kinetics; Molecular Sequence Data; Mutation; Osteosarcoma; Procollagen; Procollagen N-Endopeptidase; Protein Precursors; Recombinant Proteins; RNA, Messenger; Skin; Substrate Specificity; Transfection; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Cells, Cultured

Decorin belongs to a family of small leucine-rich dermatan sulfate proteoglycans that are involved in the control of matrix organization and cell growth. Here, we described a patient whose skin glycosaminoglycans showed extremely decreased amount of dermatan sulfate compared with a normal control skin. This patient presented clinical features of Ehlers-Danlos syndrome with a chronic skin ulcer. Western blotting revealed that the deficiency of dermatan sulfate was due to the defect of decorin core protein. Beta-xyloside, an initiator of dermatan sulfate glycosaminoglycan chain elongation, enhanced the synthesis of dermatan sulfate in the fibroblasts of the patient to a similar extent to that of control. This result indicated that the enzymes for the elogation of dermatan sulfate side chains were normal. Northern blotting demonstrated remarkable reduction of decorin mRNA level, while biglycan mRNA level was concomitantly increased and procollagen alpha1(I) mRNA level was normal. cDNA and exons sequencing analysis showed there was no mutation in decorin gene of the patient. IL-1beta stimulated decorin expression to about 140% in control fibroblasts while about 110% in patient fibroblasts. On the other hand, TGF-beta1 resulted in 40% reductions of decorin expression in both control and patient fibroblasts. These data suggested that reduced decorin expression of fibroblasts from the patient of Ehlers-Danlos syndrome may be due to abnormalities in the regulatory regions, which is responsible for the IL-1beta stimulation.

Topics: Asian People; Chronic Disease; Decorin; Ehlers-Danlos Syndrome; Extracellular Matrix Proteins; Female; Fibroblasts; Gene Expression Regulation; Genetic Variation; Glycosaminoglycans; Humans; Interleukin-1; Japan; Mastectomy; Middle Aged; Postoperative Complications; Proteoglycans; Reverse Transcriptase Polymerase Chain Reaction; Skin Ulcer; Transcription, Genetic; Transforming Growth Factor beta