Decorin Modulates Fibrin Assembly and Structure

Dugan, Tracey A.; Yang, Vivian W.-C.; McQuillan, David J.; Höök, Magnus

doi:10.1074/jbc.m607244200

Cited by 39 publications

(31 citation statements)

References 80 publications

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“…Similarly, decorin and biglycan, proteoglycans involved in the purported inhibition and/or regulation of collagen fibril and fibrin assembly (10,12,43), demonstrated a significantly greater expression in the 7-wk HLU-group compared with the Amb-healing group, suggesting that normal fibrillogenesis in the HLU-healing animals may be compromised. The importance of decorin gene and protein expression in ligament healing needs further study.…”

Section: Differential Expression Extracellular Matrix Genes During LImentioning

confidence: 98%

Temporal extracellular matrix adaptations in ligament during wound healing and hindlimb unloading

Martinez¹,

Vailas²,

Vanderby³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Martinez DA, Vailas AC, Vanderby R Jr, Grindeland RE. Temporal extracellular matrix adaptations in ligament during wound healing and hindlimb unloading. Am J Physiol Regul Integr Comp Physiol 293: R1552-R1560, 2007. First published August 15, 2007 doi:10.1152/ajpregu.00423.2007.-Previous data from spaceflight studies indicate that injured muscle and bone heal slowly and abnormally compared with ground controls, strongly suggesting that ligaments or tendons may not repair optimally as well. Thus the objective of this study was to investigate the biochemical and molecular gene expression of the collagen extracellular matrix in response to medial collateral ligament (MCL) injury repair in hindlimb unloaded (HLU) rodents. Male rats were assigned to 3-and 7-wk treatment groups with three subgroups each: sham control, ambulatory healing (Amb-healing), and HLU-healing groups. Amb-and HLU-healing animals underwent bilateral surgical transection of their MCLs, whereas control animals were subjected to sham surgeries. All surgeries were performed under isoflurane anesthesia. After 3 wk or 7 wk of HLU, rats were euthanized and MCLs were surgically isolated and prepared for molecular or biochemical analyses. Hydroxyproline concentration and hydroxylysylpyridinoline collagen cross-link contents were measured by HPLC and showed a substantial decrement in surgical groups. MCL tissue cellularity, quantified by DNA content, remained significantly elevated in all HLU-healing groups vs. Amb-healing groups. MCL gene expression of collagen type I, collagen type III, collagen type V, fibronectin, decorin, biglycan, lysyl oxidase, matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-1, measured by real-time quantitative PCR, demonstrated differential expression in the HLU-healing groups compared with Ambhealing groups at both the 3-and 7-wk time points. Together, these data suggest that HLU affects dense fibrous connective tissue wound healing and confirms previous morphological and biomechanical data that HLU inhibits the ligament repair processes.

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Section: Differential Expression Extracellular Matrix Genes During LImentioning

confidence: 98%

Temporal extracellular matrix adaptations in ligament during wound healing and hindlimb unloading

Martinez¹,

Vailas²,

Vanderby³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…1 Variables known to influence fibrin clot structure include fibrinogen and thrombin concentrations, 1 pH, 2,3 ionic strength, 3 chloride ion concentration, 2 and presence of calcium ions. 4 A variety of molecules are reported to affect fibrin clot structure, including homocysteine, 5 decorin core protein, 6 heparins, 7,8 dextran, 9 and hydroxyethylstarch. 10 In this study, we demonstrate that inorganic polyphosphate (polyP) strongly modulates fibrin clot structure.…”

Section: Introductionmentioning

confidence: 99%

Polyphosphate enhances fibrin clot structure

Smith

Morrissey

2008

Blood

192

185

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Polyphosphate, a linear polymer of inorganic phosphate, is present in platelet dense granules and is secreted on platelet activation. We recently reported that polyphosphate is a potent hemostatic regulator, serving to activate the contact pathway of blood clotting and accelerate factor V activation. Because polyphosphate did not alter thrombin clotting times, it appeared to exert all its procoagulant actions upstream of thrombin. We now report that polyphosphate enhances fibrin clot structure in a calciumdependent manner. Fibrin clots formed in the presence of polyphosphate had up to 3-fold higher turbidity, had higher masslength ratios, and exhibited thicker fibers in scanning electron micrographs. The ability of polyphosphate to enhance fibrin clot turbidity was independent of factor XIIIa activity. When plasmin or a combination of plasminogen and tissue plasminogen activators were included in clotting reactions, fibrin clots formed in the presence of polyphosphate exhibited prolonged clot lysis times. Release of polyphosphate from activated platelets or infectious microorganisms may play an important role in modulating fibrin clot structure and increasing its resistance to fibrinolysis. Polyphosphate may also be useful in enhancing the structure of surgical fibrin sealants. (Blood. 2008;112: 2810-2816) IntroductionA fibrin clot is the final product of the blood clotting cascade. Thrombin catalyzes release of fibrinopeptide A from fibrinogen to create fibrin monomers, which then aggregate to protofibrils. Proteolytic release of fibrinopeptide B by thrombin permits lateral protofibril aggregation, resulting in a three-dimensional fibrin gel. Factor XIIIa, a transglutaminase activated by thrombin, covalently crosslinks these fibers to increase the strength and elasticity of the resulting clot. 1 Variables known to influence fibrin clot structure include fibrinogen and thrombin concentrations, 1 pH, 2,3 ionic strength, 3 chloride ion concentration, 2 and presence of calcium ions. 4 A variety of molecules are reported to affect fibrin clot structure, including homocysteine, 5 decorin core protein, 6 heparins, 7,8 dextran, 9 and hydroxyethylstarch. 10 In this study, we demonstrate that inorganic polyphosphate (polyP) strongly modulates fibrin clot structure.polyP is a negatively charged, linear polymer of phosphate units linked by high-energy phosphoanhydride bonds. polyP has a wide biologic distribution, 11 but its functions have been studied most extensively in prokaryotes and unicellular eukaryotes, in which high levels of polyP accumulate in organelles known as acidocalcisomes. In such organisms, polyP plays essential roles in stress responses and virulence. 12 Although polyP has been studied less extensively in mammalian cells, 13 it has been reported to induce apoptosis in plasma cells, 14 promote calcification in osteoblasts, 15 and block metastasis of melanoma cells in a mouse model. 16 It has also been proposed to serve as a regulatory factor in proliferative signaling pathways. 17 Dense granules of human...

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“…Recently described examples include the decorin and platelet factor-4. 35,36 Furthermore, STAT5 is known to be involved in a number of signaling pathways including prolactin, interleukin-2 (IL-2), IL-3, IL-5, insulin, and epidermal growth factor signaling. Others have shown that there are dramatic changes in the expression of genes/proteins in the livers of STAT5-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Increased thrombosis susceptibility and altered fibrin formation in STAT5-deficient mice

Nordstrom

Holliday

Sos

et al. 2010

Blood

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To explore the effect(s) of growth hormone signaling on thrombosis, we studied signal transduction and transcription factor 5 (STAT5)-deficient mice and found markedly reduced survival in an in vivo thrombosis model. These findings were not explained by a compensatory increase in growth hormone secretion. There was a modest increase in the activity of several procoagulant factors, but there was no difference in the rate or magnitude of thrombin generation in STAT5-deficient mice relative to control.However, thrombin-triggered clot times were markedly shorter, and fibrin polymerization occurred more rapidly in plasma from STAT5-deficient mice. Fibrinogen depletion and mixing studies indicated that the effect on fibrin polymerization was not due to intrinsic changes in fibrinogen, but resulted from changes in the concentration of a circulating plasma inhibitor. While thrombin-triggered clot times were significantly shorter in STAT5-deficient animals, reptilase-triggered clot times were unchanged. Accordingly, while the rate of thrombin-catalyzed release of fibrinopeptide A was similar, the release of fibrinopeptide B was accelerated in STAT5-deficient plasma versus control. Taken IntroductionThrombosis-related diseases such as myocardial infarction, stroke, and venous thromboembolism account for substantial morbidity and mortality worldwide. We recently demonstrated that thrombosis susceptibility is mediated, in part, by sex-specific patterns of growth hormone (GH) secretion and subsequent effects on expression of coagulation-related genes in the liver. 1 GH is a pleiotropic hormone that is synthesized and secreted by the anterior pituitary gland and has diverse effects on its target tissues. 2,3 Hepatic GH signaling occurs via the type I cytokine receptor, growth hormone receptor, and activation of its primary downstream effectors, the Janus kinase 2 (JAK2) and signal transduction and transcription factor 5 (STAT5). Mice deficient in both STAT5A and STAT5B are largely insensitive to GH and consequently, have an impaired insulin-like growth factor 1-mediated feedback inhibition and dysregulated GH secretion. [4][5][6][7][8] STAT5 is also an integral component of interleukin, erythropoietin, and prolactin signaling pathways. Furthermore, STAT5 can be activated independently of JAK2 by receptor tyrosine kinases and other mechanisms. 9,10 STAT5 has thus been shown to be a central component of GH signaling, as well as other important cytokine signaling pathways.Previously, we demonstrated that GH-deficient little mice are protected from thrombosis in vivo. 1 Considering the important role of STAT5 in GH signaling, we aimed to study the role of STAT5 in thrombosis. In this study, we characterized 2 mouse models of STAT5 deficiency. We predicted that mice deficient in STAT5 would have a decrease in thrombosis susceptibility, as seen in GH-deficient little mice. Surprisingly, we found that the genetic loss of STAT5 resulted in increased susceptibility to thrombosis, in vivo, and shortened clotting times, in vitro. These...

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Decorin Modulates Fibrin Assembly and Structure

Cited by 39 publications

References 80 publications

Temporal extracellular matrix adaptations in ligament during wound healing and hindlimb unloading

Temporal extracellular matrix adaptations in ligament during wound healing and hindlimb unloading

Polyphosphate enhances fibrin clot structure

Increased thrombosis susceptibility and altered fibrin formation in STAT5-deficient mice

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