Molecular alterations due to Col5a1 Haploinsufficiency in a mouse model of classic Ehlers Danlos syndrome

2021 ◽  
Author(s):  
Keren Machol ◽  
Urszula Polak ◽  
Monika Weisz-Hubshman ◽  
I-Wen Song ◽  
Shan Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Type I Collagen ◽  
Lysyl Oxidase ◽  
Type I ◽  
Ehlers Danlos Syndrome ◽  
Type V Collagen ◽  
Molecular Alterations ◽  
Extracellular Matrix Components ◽  
Type V ◽  
Danlos Syndrome

Abstract 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. 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 is 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 extracellular matrix components including thrombospondin-1, lysyl oxidase, and lumican in the skin of Col5a1+/− mice when compared to control. We also identified upregulation of Tgf-β in serum and increased expression of pSmad2 in skin from Col5a1+/− mice suggesting Tgf-β dysregulation as a contributor for abnormal wound healing and atrophic scaring 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 treatment of the disease.

scholarly journals Interactions of thrombospondin with extracellular matrix proteins: selective binding to type V collagen.

1984 ◽  
Vol 98 (2) ◽  
pp. 646-652 ◽  
Author(s):  
S M Mumby ◽  
G J Raugi ◽  
P Bornstein
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Immunosorbent Assay ◽  
Type I Collagen ◽  
Cultured Cells ◽  
Serum Proteins ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Type V Collagen ◽  
Type V

Thrombospondin (TS), a protein first described in platelets, was recently shown to be synthesized and secreted by endothelial cells, fibroblasts, and smooth muscle cells. The presence of TS in the extracellular matrix of cultured cells has prompted us to examine the associations of this protein with matrix macromolecules. Interactions of TS with both matrix and serum proteins were tested using an enzyme-linked immunosorbent assay. With this assay we assessed the binding of TS in solution to proteins adsorbed to polystyrene microtiter plates. Among collagens, platelet TS bound to type V but not to types I, III, or IV. This selective interaction was confirmed in experiments using proteins linked to cyanogen bromide-activated Sepharose. TS released from platelets in response to thrombin activation, as well as that secreted by endothelial cells in culture, bound to type V but not to type I collagen-Sepharose. No binding was observed to denatured type V collagen-Sepharose. The binding region for type V collagen was located in a chymotrypsin-produced fragment of TS with chains of Mr = 70,000, after reduction. Interactions of TS with a number of other proteins, including fibronectin, fibrinogen, and laminin, could be demonstrated using the enzyme-linked immunosorbent assay technique but the interpretation of these findings is difficult since comparable binding to protein-Sepharose was not always observed. Our findings suggest that both the extravascular distribution and function of TS in vivo may involve an interaction with type V collagen.

Collagen fibrillogenesis in vitro: interaction of types I and V collagen

1986 ◽  
Vol 44 ◽  
pp. 210-211
Author(s):  
Arthur J. Wasserman ◽  
Kathy C. Kloos ◽  
David E. Birk
Keyword(s):  
Type I Collagen ◽  
Corneal Stroma ◽  
Minor Component ◽  
Homogeneous Distribution ◽  
Type I ◽  
Type V Collagen ◽  
Fibril Morphology ◽  
Type V ◽  
In Vitro Interaction

Type I collagen is the predominant collagen in the cornea with type V collagen being a quantitatively minor component. However, the content of type V collagen (10-20%) in the cornea is high when compared to other tissues containing predominantly type I collagen. The corneal stroma has a homogeneous distribution of these two collagens, however, immunochemical localization of type V collagen requires the disruption of type I collagen structure. This indicates that these collagens may be arranged as heterpolymeric fibrils. This arrangement may be responsible for the control of fibril diameter necessary for corneal transparency. The purpose of this work is to study the in vitro assembly of collagen type V and to determine whether the interactions of these collagens influence fibril morphology.

scholarly journals Ultrastructural localization of type V collagen in rat kidney.

1982 ◽  
Vol 92 (2) ◽  
pp. 343-349 ◽  
Author(s):  
A Martinez-Hernandez ◽  
S Gay ◽  
E J Miller
Keyword(s):  
Type I Collagen ◽  
Rat Kidney ◽  
Ultrastructural Localization ◽  
Particulate Material ◽  
Basement Membranes ◽  
Type I ◽  
Type V Collagen ◽  
Collagen Molecules ◽  
Immunohistochemical Studies ◽  
Type V

Antibodies specific for the alpha 1 (V) chain and native collagen molecules containing the alpha 1 (V) chain have been used in electron immunohistochemical studies of rat kidney to determine the ultrastructural distribution of this class of collagen molecules. In addition, antibodies against type I collagen and whole basement membrane were used as markers for interstitial collagen and authentic basement membranes. Our results indicate that type V collagen is present in the renal interstitium in different forms: in close apposition to interstitial collagen fibers; in the stromal aspect of vascular basement membranes; and as particulate material not bound to other structures. On the basis of these findings, we postulate a binding or connecting function for this collagen type.

Collagen fibrillogenesis in vitro: interaction of types I and V collagen regulates fibril diameter

1990 ◽  
Vol 95 (4) ◽  
pp. 649-657 ◽  
Author(s):  
D.E. Birk ◽  
J.M. Fitch ◽  
J.P. Babiarz ◽  
K.J. Doane ◽  
T.F. Linsenmayer
Keyword(s):  
Type I Collagen ◽  
Small Diameter ◽  
Collagen Molecule ◽  
Type I ◽  
Collagen Types ◽  
Type V Collagen ◽  
Amino Terminal ◽  
Type V ◽  
Fibril Diameter

The small-diameter fibrils of the chick corneal stroma are heterotypic, composed of both collagen types I and V. This tissue has a high concentration of type V collagen relative to other type I-containing tissues with larger-diameter fibrils, suggesting that heterotypic interactions may have a regulatory role in the control of fibril diameter. The interactions of collagen types I and V were studied using an in vitro self-assembly system. Collagens were purified from lathyritic chick embryos in the presence of protease inhibitors. The type V collagen preparations contained higher molecular weight forms of the alpha 1(V) and alpha 2(V) chains constituting 60–70% of the total. Rotary-shadow electron micrographs showed a persistence of a small, pepsin-sensitive terminal region in an amount consistent with that seen by electrophoresis. In vitro, this purified type V collagen formed thin fibrils with no apparent periodicity, while type I collagen fibrils had a broad distribution of large diameters. However, when type I collagen was mixed with increasing amounts of type V collagen a progressive and significant decrease in both the mean fibril diameter and the variance was observed for D periodic fibrils. The amino-terminal domain of the type V collagen molecule was required for this regulatory effect and in its absence little diameter reducing activity was observed. Electron microscopy using collagen type-specific monoclonal antibodies demonstrated that the fibrils formed were heterotypic, containing both collagen types I and V. These data indicate that the interaction of type V with type I collagen is one mechanism modulating fibril diameter and is at least partially responsible for the regulation of collagen fibril formation.

scholarly journals TEF-1 and C/EBPβ are major p38α MAPK-regulated transcription factors in proliferating cardiomyocytes

2006 ◽  
Vol 396 (1) ◽  
pp. 163-172 ◽  
Author(s):  
Concetta Ambrosino ◽  
Tomoko Iwata ◽  
Claudio Scafoglio ◽  
Massimo Mallardo ◽  
Rüdiger Klein ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factors ◽  
Environmental Stress ◽  
Type I Collagen ◽  
Specific Gene ◽  
Type I ◽  
Transcriptional Enhancer ◽  
Extracellular Matrix Components ◽  
Mitogen Activated Protein ◽  
P38 Mapks

p38 MAPKs (mitogen-activated protein kinases) play important roles in the regulation of cellular responses to environmental stress. Recently, this signalling pathway has also been implicated in the regulation of processes unrelated to stress, for example, in T lymphocytes and cardiomyocytes. In order to identify molecular targets responsible for the housekeeping functions of p38 MAPKs, we have analysed the differences in the transcriptomes of normally proliferating wild-type and p38α knockout immortalized embryonic cardiomyocytes. Interestingly, many potential components of the myocardium extracellular matrix were found to be upregulated in the absence of p38α. Further analysis of the microarray data identified TEF-1 (transcriptional enhancer factor-1), a known regulator of heart-specific gene expression, and C/EBPβ (CCAAT/enhancer-binding protein β), as the two transcription factors the binding sites of which were most enriched in the promoters of p38α-regulated genes. We have focused on the study of the extracellular matrix component COL1A1 (α1 chain of type I collagen) and found evidence for the involvement of both TEF-1 and C/EBPβ in the p38α-dependent inhibition of COL1A1 transcription. Our data therefore show that p38 MAPKs regulate TEF-1 and C/EBPβ transcriptional activity in the absence of environmental stress and suggests a role for p38α in the expression of extracellular matrix components that maintain organ architecture.

Lysyl Oxidase Deficiency in Ehlers–Danlos Syndrome Type V

1975 ◽  
Vol 3 (1) ◽  
pp. 49-53 ◽  
Author(s):  
N. Di Ferrante ◽  
R. D. Leachman ◽  
P. Angelini ◽  
P. V. Donnelly ◽  
G. Francis ◽  
...  
Keyword(s):  
Lysyl Oxidase ◽  
Syndrome Type ◽  
Oxidase Deficiency ◽  
Ehlers Danlos Syndrome ◽  
Type V ◽  
Danlos Syndrome
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