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The Journal of Biological Chemistry Mar 2009Extracellular thrombospondins (TSP or THBS) and the Notch family of transmembrane receptors share a role in multiple, overlapping cellular functions and participate in...
Extracellular thrombospondins (TSP or THBS) and the Notch family of transmembrane receptors share a role in multiple, overlapping cellular functions and participate in developmental signaling and pathological reactions to tissue injury. We demonstrate that TSP2, but not TSP1, enhances the potency of Notch3 signal transduction. In addition, TSP2 reduces cancer cell proliferation in a Notch-ligand dependent fashion. The loss of TSP2 in knock-out mice reduces Notch target gene expression. TSP2 binds directly to Notch3 and Jagged1. TSP1 also binds to Notch3 and Jagged1; however, only TSP2 augments the interaction between Notch3 and Jagged1. These studies demonstrate that the diverse functions of TSP2 may also include a role as an intermediary protein that facilitates transcellular receptor-ligand interactions.
Topics: Animals; Calcium-Binding Proteins; Cell Line, Tumor; Gene Expression Regulation; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Mice; Mice, Knockout; Receptor, Notch3; Receptors, Notch; Serrate-Jagged Proteins; Signal Transduction; Thrombospondin 1; Thrombospondins
PubMed: 19147503
DOI: 10.1074/jbc.M803650200 -
Liver International : Official Journal... Mar 2021Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in...
AIM
Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in various functions such as collagen/fibrin formation, maintenance of normal blood vessel density and cell adhesion properties. Microarray analyses ranked TSP2 as one of the most highly up-regulated genes in the fibrotic liver in patients with non-alcoholic fatty liver disease (NAFLD). Since TSP2 possesses unique properties as a secretory protein, we hypothesized that hepatic TSP2 gene expression levels would be reflected in serum TSP2 levels. In this study, we examined the relationship between serum TSP2 concentrations and clinicopathological findings in NAFLD patients.
METHODS
One hundred and thirty NAFLD patients who had undergone liver biopsy between 2009 and 2015 were retrospectively enrolled. Serum samples were collected at the time of biopsy, and TSP2 was measured by enzyme immunoassays.
RESULTS
Serum TSP2 levels moderately correlated with ballooning (r = 0.56, P < .001) and fibrosis stage (r = 0.53, P < .001). The AUC values of TSP2 for predicting mild fibrosis (≧F1), moderate fibrosis (≧F2) and severe fibrosis (≧F3) were 0.73, 0.76 and 0.82 respectively. Additionally, NAFLD activity score (NAS) correlated best with TSP2 (r = 0.52, P < .001) compared to conventional NAFLD-related biomarkers, such as cytokeratin 18 M30, hyaluronic acid, type IV collagen 7S, APRI and FIB-4 index.
CONCLUSION
Serum TSP2 levels reflected hepatocyte ballooning, fibrosis and NAS in NAFLD patients. For clinical application of serum TSP2 as a predictor of NAFLD histological activity, additional validation and mechanistic investigations are required.
Topics: Biomarkers; Biopsy; Humans; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Retrospective Studies; Thrombospondins
PubMed: 33386676
DOI: 10.1111/liv.14776 -
Biochemical and Biophysical Research... Nov 2020Critical limb ischemia (CLI) is the leading cause of lower limb amputation. Traditional treatments for CLI have limitations. Studies have shown that thrombospondin-4...
Critical limb ischemia (CLI) is the leading cause of lower limb amputation. Traditional treatments for CLI have limitations. Studies have shown that thrombospondin-4 (TSP4) can promote the growth of neovascularization. In this study, we observed the angiogenesis efficiency of TSP4-overexpressing BMSC transplantation in CLI treatment. The recombinant FT106-tsp4-gfp lentiviral vector plasmid was constructed and transfected into 293FT cells. Primary BMSCs were successfully infected with the tsp4 virus, and TSP4 overexpression was confirmed before TSP4-BMSCs infusion. A rat CLI model was established, and 60 CLI rats were randomly divided into the CLI, BMSC + CLI and TSP4-BMSC + CLI groups. The effect of TSP4-BMSC on angiogenesis was detected by the motor function, immunohistochemistry and immunofluorescence staining assays. Neovascular density was detected by digital subtraction angiography (DSA). Our results demonstrated that TSP4-BMSCs improved the motor function score of the CLI rats and increased MMP2, MMP9, Ang-1, VEGF and vWF protein expression in tissue of the ischaemic area. Meanwhile, new blood vessels can be observed around the ischemic area after TSP4-BMSCs treatment. Our data illustrate that TSP4-BMSCs can promote the recovery of motor function in diabetic hind limb ischaemic rats. TSP4-BMSCs have better therapeutic effects than BMSCs.
Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Disease Models, Animal; Extremities; Ischemia; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Neovascularization, Physiologic; Rats, Sprague-Dawley; Recombinant Proteins; Thrombospondins
PubMed: 32868074
DOI: 10.1016/j.bbrc.2020.06.148 -
European Journal of Cell Biology Jun 2024Pain is the most common symptom for which patients seek medical attention. Existing treatments for pain control are largely ineffective due to the lack of an accurate...
Pain is the most common symptom for which patients seek medical attention. Existing treatments for pain control are largely ineffective due to the lack of an accurate way to objectively measure pain intensity and a poor understanding of the etiology of pain. Thrombospondin 4(TSP4), a member of the thrombospondin gene family, is expressed in neurons and astrocytes and induces pain by interacting with the calcium channel alpha-2-delta-1 subunit (Cavα2δ1). In the present study we show that TSP4 expression level correlates positively with pain intensity, suggesting that TSP4 could be a novel candidate of pain indicator. Using RNAi-lentivirus (RNAi-LV) to knock down TSP4 both in vivo and in vitro, together with electrophysiological experiments involving paired patch-clamp recordings of evoked action potentials and post-synaptic currents in cultured neurons, we found that TSP4 contributes to the development of bone cancer pain, neuropathic pain, and inflammatory pain. This effect is mediated by regulation of neuron excitability via inhibition of synapsin I (Syn I) and modulation of excitatory and inhibitory presynaptic transmission via regulation of vesicular glutamate transporter 2(Vglut2), vesicular GABA transporter (VGAT), and glutamate decarboxylase (GAD) expression. The present study provides a replicable, predictive, valid indicator of pain and demonstrated the underlying molecular and electrophysiological mechanisms by which TSP4 contributes to pain.
Topics: Animals; Thrombospondins; Male; Pain; Neurons; Mice; Humans; Female; Bone Neoplasms
PubMed: 38340499
DOI: 10.1016/j.ejcb.2024.151395 -
Experimental Eye Research Dec 2019Elevated intraocular pressure (IOP) is a major risk factor for the development of primary open-angle glaucoma (POAG). This is from an increased aqueous humour (AH)...
Elevated intraocular pressure (IOP) is a major risk factor for the development of primary open-angle glaucoma (POAG). This is from an increased aqueous humour (AH) outflow resistance through the trabecular meshwork (TM). The pathogenic mechanisms leading to the increase in TM outflow resistance are poorly understood but are thought to be from a dysregulation of the TM extracellular matrix (ECM) environment. ECM modification and turnover are crucial in regulating the resistance to aqueous outflow. ECM turnover is influenced by a complex interplay of growth factors such as transforming growth factors (TGFβ) family and matrix metalloproteinases (MMPs). Elevated TGFβ2 levels result in an increase in ECM deposition such as fibronectin leading to increased resistance. Fibronectin is a major component of TM ECM and plays a key role in its maintenance. Thrombospondins (TSP)-1 and -2 are important regulators of the ECM environment. TSP-1 has been implicated in the pathogenesis of POAG through activation of TGFβ2 within the TM. TSP-2 does not contain the catalytic domain to activate latent TGFβ, but is able to mediate the activities of MMP 2 and 9, thereby influencing ECM turnover. TSP-2 knock out mice show lower IOP levels compared to their wild type counterparts, suggesting the involvement of TSP-2 in the pathogenesis of POAG but its role in the pathogenesis of POAG remains unclear. The purpose of this study was to investigate the role of TSP-2 in trabecular meshwork ECM regulation and hence the pathogenesis of POAG. TSP-1 and TSP-2 expressions in immortalised glaucomatous TM cells (GTM3) and primary human non-glaucomatous (NTM) and glaucomatous cells (GTM) were determined by immunocytochemistry, immuno-blot analysis and qPCR following treatment with TGFβ2 and Dexamethasone. The level of ECM protein fibronectin was determined in TM cells using immuno-blot analysis following treatment with TSP-1 or -2. TM cells secrete TSP-1 and -2 under basal conditions at the protein level and TSP-2 mRNA and protein levels were increased in response to TGFβ2 three days post treatment. Exogenous treatment with TSP-2 up-regulated the expression of fibronectin protein in GTM3 cells, primary NTM and GTM cells. TSP-1 did not affect fibronectin protein levels in GTM3 cells. This suggests that the role of TSP-2 might be distinct from that of TSP-1 in the regulation of the TM cell ECM environment. TSP-2 may be involved in the pathogenesis of POAG and contribute to increased IOP levels by increasing the deposition of fibronectin within the ECM in response to TGFβ2.
Topics: Cell Adhesion Molecules; Cells, Cultured; Fibronectins; Gene Expression Regulation; Glaucoma, Open-Angle; Humans; Intraocular Pressure; RNA, Messenger; Thrombospondins; Trabecular Meshwork; Transforming Growth Factor beta2; Up-Regulation
PubMed: 31589839
DOI: 10.1016/j.exer.2019.107820 -
Current Drug Targets Oct 2008The past decades have been marked by spectacular progress towards understanding how dendritic cells (DCs) interact with T cells to elicit protective immune responses to... (Review)
Review
The past decades have been marked by spectacular progress towards understanding how dendritic cells (DCs) interact with T cells to elicit protective immune responses to fight infectious diseases and cancer. DCs that are lying at the interface between innate and adaptive immunity, are educated in peripheral tissues prior to their journey to the secondary lymphoid organs (SLO) whereby they dictate different classes of T cell responses. Uncontrolled or unwanted inflammatory responses are the price to pay to eliminate pathogens. However, if not self-limited, they may induce collateral damages that result in chronic inflammation often associated with autoimmune disorders. CD47 and its two ligands, i.e. thrombospondin 1 (TSP-1) and SIRP-alpha, were identified as a previously unappreciated inhibitory axis of DC and T cell functions. TSP-1 is predominantly a negative regulator of DC and T cell function while basal SIRP-alpha ligation on APC by CD47 enforces tolerance. Yet, CD47/SIRP-alpha interaction positively controls DC and innate cell transendothelial migration. Due to the promiscuity of the protein interactions for CD47 and its ligands, it is quite interesting to note that deletion of the CD47 gene in mice largely agrees with the in vitro data with human cells. In fact, the well-conserved tissue distribution of CD47 and SIRP-alpha across species may facilitate the transition from bench to bedside. We thus propose CD47/TSP-1/SIRP-alpha axis as an important sensor to maintain homeostasis and regulate innate and adaptive immune responses.
Topics: Animals; Antigens, Differentiation; CD47 Antigen; Homeostasis; Humans; Immunity, Innate; Receptors, Immunologic; Signal Transduction; Thrombospondins
PubMed: 18855618
DOI: 10.2174/138945008785909310 -
Journal of Musculoskeletal & Neuronal... 2006
Review
Topics: Animals; Bone Development; Bone Regeneration; Bone Remodeling; Extracellular Matrix; Mice; Mice, Knockout; Osteoblasts; Thrombospondins
PubMed: 17185828
DOI: No ID Found -
The New England Journal of Medicine Mar 2015
Topics: Autoantibodies; Glomerulonephritis, Membranous; Humans; Receptors, Phospholipase A2; Thrombospondins
PubMed: 25760365
DOI: 10.1056/NEJMc1500130 -
The New England Journal of Medicine Mar 2015
Topics: Autoantibodies; Glomerulonephritis, Membranous; Humans; Receptors, Phospholipase A2; Thrombospondins
PubMed: 25760364
DOI: 10.1056/NEJMc1500130 -
FASEB Journal : Official Publication of... Sep 2020Thrombospondin-4 (TSP4) is a pro-angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP...
Thrombospondin-4 (TSP4) is a pro-angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP variant, P387 TSP4, have been associated with cardiovascular disease. Macrophages are central to initiation and resolution of inflammation and development of atherosclerotic lesions, but the effects of the P387 TSP4 on macrophages remain essentially unknown. We examined the effects of the P387 TSP4 variant on macrophages in cell culture and in vivo in a murine model of atherosclerosis. Furthermore, the levels and distributions of the two TSP4 variants were assessed in human atherosclerotic arteries. In ApoE /P387-TSP4 knock-in mice, lesions size measured by Oil Red O did not change, but the lesions accumulated more macrophages than lesions bearing A387 TSP4. The levels of inflammatory markers were increased in lesions of ApoE /P387-TSP4 knock-in mice compared to ApoE mice. Lesions in human arteries from individuals carrying the P387 variant had higher levels of TSP4 and higher macrophage accumulation. P387 TSP4 was more active in supporting adhesion of cultured human and mouse macrophages in experiments using recombinant TSP4 variants and in cells derived from P387-TSP4 knock-in mice. TSP4 supports the adhesion of macrophages and their accumulation in atherosclerotic lesions without changing the size of lesions. P387 TSP4 is more active in supporting these pro-inflammatory events in the vascular wall, which may contribute to the increased association of P387 TSP4 with cardiovascular disease.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Cell Line; Cells, Cultured; Cytokines; Disease Models, Animal; Humans; Inflammation Mediators; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Plaque, Atherosclerotic; Polymorphism, Single Nucleotide; Thrombospondins
PubMed: 32686880
DOI: 10.1096/fj.201901434RRRR