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Journal of Cellular and Molecular... 2002Thrombospondin-1 (TSP-1) is a matricellular glycoprotein that influences cellular phenotype and the structure of the extracellular matrix. These effects are important... (Review)
Review
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein that influences cellular phenotype and the structure of the extracellular matrix. These effects are important components of the tissue remodeling that is associated with angiogenesis and neoplasia. The genetic mutations in oncogenes and tumor suppressor genes that occur within tumor cells are frequently associated with decreased expression of TSP-1. However, the TSP-1 that is produced by stromal fibroblasts, endothelial cells and immune cells suppresses tumor progression. TSP-1 inhibits angiogenesis through direct effects on endothelial cell migration and survival and through indirect effects on growth factor mobilization. TSP-1 that is present in the tumor microenvironment also acts to suppress tumor cell growth through activation of transforming growth factor beta in those tumor cells that are responsive to TGF beta. In this review, the molecular basis for the role of TSP-1 in the inhibition of tumor growth and angiogenesis is summarized.
Topics: Amino Acid Sequence; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Division; Disease Progression; Enzyme Inhibitors; Models, Biological; Molecular Sequence Data; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Thrombospondin 1; Transforming Growth Factor beta
PubMed: 12003665
DOI: 10.1111/j.1582-4934.2002.tb00307.x -
Matrix Biology : Journal of the... Jul 2014R-spondins are a family of four matricellular proteins produced by a variety of cell-types. Structurally, R-spondins contain a TSR1 domain that retains the tryptophan... (Review)
Review
R-spondins are a family of four matricellular proteins produced by a variety of cell-types. Structurally, R-spondins contain a TSR1 domain that retains the tryptophan structure and a modified cysteine-rich CSVCTG region. In addition, the R-spondins contain two furin repeats implicated in canonical Wnt signaling. R-spondins positively regulate canonical Wnt signaling by reducing Wnt receptor turnover and thereby increasing beta-catenin stabilization. R-spondins are prominently expressed in the developing skeleton and contribute to limb formation, particularly of the distal digit. Additionally, results suggest that R-spondins may contribute to the maintenance of adult bone mass by regulating osteoblastogenesis and bone formation.
Topics: Amino Acid Motifs; Extracellular Matrix Proteins; Humans; Intercellular Signaling Peptides and Proteins; Models, Biological; Molecular Sequence Data; Osteogenesis; Protein Structure, Tertiary; Thrombospondins; Wnt Signaling Pathway; beta Catenin
PubMed: 24980904
DOI: 10.1016/j.matbio.2014.06.003 -
The Journal of Investigative... Dec 2000Thrombospondin 2 (TSP2)-null mice, generated by targeted disruption of the Thbs2 gene, display a complex phenotype that is characterized, in part, by a variety of... (Review)
Review
Thrombospondin 2 (TSP2)-null mice, generated by targeted disruption of the Thbs2 gene, display a complex phenotype that is characterized, in part, by a variety of connective tissue abnormalities and increased vascular density in skin and subcutaneous tissues. In this paper we summarize the evidence that TSP2 functions as a matricellular protein to influence cell function by modulating cell-matrix interactions, rather than acting as an integral component of the matrix. Thus, the structurally abnormal collagen fibrils detected in skin appear to be the consequence of the defective adhesion demonstrated by dermal fibroblasts in culture that, in turn, result from increased matrix metalloproteinase 2 (MMP2, gelatinase A) production by these cells. Corroborating evidence for such a mode of action comes from transmission electron microscopic images of developing flexor muscle tendons that show distinct abnormalities in fibroblast-collagen fibril interactions in TSP2-null tissue. The increased vascular density seen in skin of TSP2-null mice can be reproduced in a number of models of injury, including subcutaneous implantation of polyvinyl alcohol sponges and silicone rubber discs, and excisional skin wounds. Experiments are proposed to distinguish between a primarily endothelial cell versus an extracellular matrix origin for the increased angiogenesis in TSP2-null mice.
Topics: Animals; Collagen; Humans; Mice; Mice, Knockout; Neovascularization, Physiologic; Skin; Thrombospondins
PubMed: 11147677
DOI: 10.1046/j.1087-0024.2000.00005.x -
Arteriosclerosis, Thrombosis, and... Sep 2015Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties...
OBJECTIVE
Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties of the 3 other TSPs, which do not contain the domains associated with the antiangiogeneic activity of TSP-1 and TSP-2, have not been explored. In our previous studies, we found that TSP-4 is expressed in the vascular matrix of blood vessels of various sizes and is especially abundant in capillaries. We sought to identify the function of TSP-4 in the regulation of angiogenesis.
APPROACH AND RESULTS
The effect of TSP-4 in in vivo angiogenesis models and its effect on angiogenesis-related properties in cultured cells were assessed using Thbs4(-/-) mice, endothelial cells (EC) derived from these mice, and recombinant TSP-4. Angiogenesis was decreased in Thbs4(-/-) mice compared with wild-type mice. TSP-4 was detected in the lumen of the growing blood vessels. Mice expressing the P387 TSP-4 variant, which was previously associated with coronary artery disease and found to be more active in its cellular interactions, displayed greater angiogenesis compared with A387 form. Lung EC from Thbs4(-/-) mice exhibited decreased adhesion, migration, and proliferation capacities compared with EC from wild-type mice. Recombinant TSP-4 promoted proliferation and the migration of EC. Integrin α2 and gabapentin receptor α2δ-1 were identified as receptors involved in regulation of EC adhesion, migration, and proliferation by TSP-4.
CONCLUSION
TSP-4, an extracellular matrix protein previously associated with tissue remodeling, is now demonstrated to possess proangiogenic activity.
Topics: Animals; Apoptosis; Cell Adhesion; Cells, Cultured; DNA; DNA Mutational Analysis; Disease Models, Animal; Female; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Thrombospondins
PubMed: 26139464
DOI: 10.1161/ATVBAHA.115.305912 -
Arteriosclerosis, Thrombosis, and... Nov 2018
Topics: ADAMTS13 Protein; Blood Platelets; Disintegrins; Humans; Purpura, Thrombotic Thrombocytopenic; Thrombosis; Thrombospondin 1; Thrombospondins
PubMed: 30354233
DOI: 10.1161/ATVBAHA.118.311863 -
Bone Sep 2021During skeletal development most bones are first formed as cartilage templates, which are gradually replaced by bone. If later in life those bones break, temporary...
During skeletal development most bones are first formed as cartilage templates, which are gradually replaced by bone. If later in life those bones break, temporary cartilage structures emerge to bridge the fractured ends, guiding the regenerative process. This bone formation process, known as endochondral ossification (EO), has been widely studied for its potential to reveal factors that might be used to treat patients with large bone defects. The extracellular matrix of cartilage consists of different types of collagens, proteoglycans and a variety of non-collagenous proteins that organise the collagen fibers in complex networks. Thrombospondin-5, also known as cartilage oligomeric matrix protein (TSP-5/COMP) is abundant in cartilage, where it has been described to enhance collagen fibrillogenesis and to interact with a variety of growth factors, matrix proteins and cellular receptors. However, very little is known about the skeletal distribution of its homologue thrombospondin-4 (TSP-4). In our study, we compared the spatiotemporal expression of TSP-5 and TSP-4 during postnatal bone formation and fracture healing. Our results indicate that in both these settings, TSP-5 distributes across all layers of the transient cartilage, while the localisation of TSP-4 is restricted to the population of hypertrophic chondrocytes. Furthermore, in fractured bones we observed TSP-4 sparsely distributed in the periosteum, while TSP-5 was absent. Last, we analysed the chemoattractant effects of the two proteins on endothelial cells and bone marrow stem cells and hypothesised that, of the two thrombospondins, only TSP-4 might promote blood vessel invasion during ossification. We conclude that TSP-4 is a novel factor involved in bone formation. These findings reveal TSP-4 as an attractive candidate to be evaluated for bone tissue engineering purposes.
Topics: Cartilage; Cartilage Oligomeric Matrix Protein; Chondrocytes; Endothelial Cells; Humans; Osteogenesis; Thrombospondins
PubMed: 33971315
DOI: 10.1016/j.bone.2021.115999 -
Scientific Reports Dec 2023To test the hypothesis that dysregulated wound healing is associated with Urogynecologic mesh complications, we collected vaginal cell secretions using vaginal swabs...
To test the hypothesis that dysregulated wound healing is associated with Urogynecologic mesh complications, we collected vaginal cell secretions using vaginal swabs after polypropylene mesh implantation in patients with (N = 39) and without (N = 40) complication. A customized multiplex immunoassay measured markers of inflammation (MCP-1, IGFBP-1, IL-2, IL-10, IL-17, PDGF-BB, bFGF, IL-1b, IL-6, IL-12p70, TNF-α), neuroinflammation (IL-1RA, TGF-β, IL-15, IL-18, IL-3, M-CSF), angiogenesis (VEGF), and matrix proteins (fibronectin, tenasin c, thrombospondin-2, lumican) between groups. Patients with complications were younger, heavier, implanted with mesh longer, and more likely to be ever smokers. A 5 kg/m BMI increase and ever-smoking were associated with a 2.4-fold and sixfold increased risk of complication, respectively. Patients with the highest tertile of bFGF, fibronectin, thrombospondin-2, TNF-β, or VEGF had an odds ratio (OR) of 11.8 for having a mesh complication while ≥ 3 elevated had an OR of 237 while controlling for age, BMI, and smoking. The highest tertile of bFGF, thrombospondin-2, and fibronectin together perfectly indicated a complication (P < 0.0001). A receiver-operator curve for high bFGF, thrombospondin-2, and fibronectin showed excellent discrimination between complications and controls (AUC 0.87). These data provide evidence of dysregulated wound healing in mesh complications. Modifiable factors provide potential targets for patient counseling and interventions.
Topics: Female; Humans; Fibronectins; Vascular Endothelial Growth Factor A; Surgical Mesh; Wound Healing; Thrombospondins
PubMed: 38052928
DOI: 10.1038/s41598-023-48388-8 -
The New England Journal of Medicine Dec 2014Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor...
BACKGROUND
Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown.
METHODS
Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis.
RESULTS
Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1-negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic membranous nephropathy who were seropositive for anti-PLA2R1 antibodies, from the 76 patients with other glomerular diseases, and from the 44 healthy controls reacted against this antigen. Although this newly identified antigen is clearly different from PLA2R1, it shares some biochemical features, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions. Mass spectrometry identified this antigen as thrombospondin type-1 domain-containing 7A (THSD7A). All reactive serum samples recognized recombinant THSD7A and immunoprecipitated THSD7A from glomerular lysates. Moreover, immunohistochemical analyses of biopsy samples from patients revealed localization of THSD7A to podocytes, and IgG eluted from one of these samples was specific for THSD7A.
CONCLUSIONS
In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition. (Funded by the French National Center for Scientific Research and others.).
Topics: Autoantibodies; Blotting, Western; Case-Control Studies; Glomerulonephritis, Membranous; Humans; Kidney Glomerulus; Receptors, Phospholipase A2; Thrombospondins
PubMed: 25394321
DOI: 10.1056/NEJMoa1409354 -
Scientific Reports Jul 2023LGR4 and LGR5 are two homologous receptors that potentiate Wnt/β-catenin signaling in response to R-spondin (RSPO) ligands. The RSPO and LGR4 complex binds to and...
LGR4 and LGR5 are two homologous receptors that potentiate Wnt/β-catenin signaling in response to R-spondin (RSPO) ligands. The RSPO and LGR4 complex binds to and inhibits activities of two related E3 ubiquitin ligases, RNF43 and ZNRF3, and thus protects Wnt receptors from the E3 ligase-mediated degradation. The RSPO and LGR5 complex, however, does not interact with the E3 ligases, and the structural basis of this difference remained unknown. Here we examined the affinities of monovalent and bivalent RSPO ligands in binding to LGR4, RNF43/ZNRF3, and LGR5 in whole cells and found unique features among the receptors and E3 ligases. Monovalent RSPO2 furin domain had much lower affinity in binding to LGR4 or RNF43/ZNRF3 than the bivalent form. In contrast, monovalent and bivalent forms had nearly identical affinity in binding to LGR5. Co-expression of ZNRF3 with LGR4 led to much higher binding affinity of the monovalent form whereas co-expression of ZNRF3 with LGR5 had no effect on the affinity. These results suggest that LGR4 and RNF43/ZNRF3 form a 2:2 dimer that accommodates bivalent binding of RSPO whereas LGR5 forms a homodimer that does not. Structural models are proposed to illustrate how RSPOs bind to LGR4, RNF43/ZNRF3, and LGR5 in whole cells.
Topics: Receptors, G-Protein-Coupled; Ligands; Wnt Signaling Pathway; Ubiquitin-Protein Ligases; Thrombospondins
PubMed: 37402772
DOI: 10.1038/s41598-023-37856-w -
Current Neuropharmacology 2017Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular... (Review)
Review
BACKGROUND
Spike-wave discharges, underlying absence seizures, are generated within a cortico-thalamo-cortical network that involves the somatosensory cortex, the reticular thalamic nucleus, and the ventrobasal thalamic nuclei. Activation of T-type voltage-sensitive calcium channels (VSCCs) contributes to the pathological oscillatory activity of this network, and some of the first-line drugs used in the treatment of absence epilepsy inhibit T-type calcium channels. The α2δ subunit is a component of high voltage-activated VSCCs (i.e., L-, N-, P/Q-, and R channels) and studies carried out in heterologous expression systems suggest that it may also associate with T channels. The α2δ subunit is also targeted by thrombospondins, which regulate synaptogenesis in the central nervous system.
OBJECTIVE
To discuss the potential role for the thrombospondin/α2δ axis in the pathophysiology of absence epilepsy.
METHODS
We searched PubMed articles for the terms "absence epilepsy", "T-type voltage-sensitive calcium channels", "α2δ subunit", "ducky mice", "pregabalin", "gabapentin", "thrombospondins", and included papers focusing this Review's scope.
RESULTS
We moved from the evidence that mice lacking the α2δ-2 subunit show absence seizures and α 2δ ligands (gabapentin and pregabalin) are detrimental in the treatment of absence epilepsy. This suggests that α2δ may be protective against absence epilepsy via a mechanism that does not involve T channels. We discuss the interaction between thrombospondins and α2δ and its potential relevance in the regulation of excitatory synaptic formation in the cortico-thalamo-cortical network.
CONCLUSION
We speculate on the possibility that the thrombospondin/α2 δ axis is critical for the correct functioning of the cortico-thalamo-cortical network, and that abnormalities in this axis may play a role in the pathophysiology of absence epilepsy.
Topics: Animals; Calcium Channels; Epilepsy, Absence; Humans; Thrombospondins
PubMed: 28290248
DOI: 10.2174/1570159X15666170309105451