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International Journal of Molecular... Mar 2021The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular... (Review)
Review
The hyalectan family is composed of the proteoglycans aggrecan, versican, brevican and neurocan. Hyalectans, also known as lecticans, are components of the extracellular matrix of different tissues and play essential roles in key biological processes including skeletal development, and they are related to the correct maintenance of the vascular and central nervous system. For instance, hyalectans participate in the organization of structures such as perineural nets and in the regulation of neurite outgrowth or brain recovery following a traumatic injury. The ADAMTS (A Disintegrin and Metalloprotease domains, with thrombospondin motifs) family consists of 19 secreted metalloproteases. These enzymes also perform important roles in the structural organization and function of the extracellular matrix through interactions with other matrix components or as a consequence of their catalytic activity. In this regard, some of their preferred substrates are the hyalectans. In fact, ADAMTSs cleave hyalectans not only as a mechanism for clearance or turnover of proteoglycans but also to generate bioactive fragments which display specific functions. In this article we review some of the physiological and pathological effects derived from cleavages of hyalectans mediated by ADAMTSs.
Topics: ADAMTS Proteins; Brain; Brain Injuries, Traumatic; Extracellular Matrix; Humans; Hyalectins; Neuronal Outgrowth; Thrombospondins; Versicans
PubMed: 33804223
DOI: 10.3390/ijms22062988 -
Biochimica Et Biophysica Acta Aug 2014Numerous proteins and small leucine-rich proteoglycans (SLRPs) make up the composition of the extracellular matrix (ECM). Assembly of individual fibrillar components in... (Review)
Review
BACKGROUND
Numerous proteins and small leucine-rich proteoglycans (SLRPs) make up the composition of the extracellular matrix (ECM). Assembly of individual fibrillar components in the ECM, such as collagen, elastin, and fibronectin, is understood at the molecular level. In contrast, the incorporation of non-fibrillar components and their functions in the ECM are not fully understood.
SCOPE OF REVIEW
This review will focus on the role of the matricellular protein thrombospondin (TSP) 2 in ECM assembly. Based on findings in TSP2-null mice and in vitro studies, we describe the participation of TSP2 in ECM assembly, cell-ECM interactions, and modulation of the levels of matrix metalloproteinases (MMPs).
MAJOR CONCLUSIONS
Evidence summarized in this review suggests that TSP2 can influence collagen fibrillogenesis without being an integral component of fibrils. Altered ECM assembly and excessive breakdown of ECM can have both positive and negative consequences including increased angiogenesis during tissue repair and compromised cardiac tissue integrity, respectively.
GENERAL SIGNIFICANCE
Proper ECM assembly is critical for maintaining cell functions and providing structural support. Lack of TSP2 is associated with increased angiogenesis, in part, due to altered endothelial cell-ECM interactions. Therefore, minor changes in ECM composition can have profound effects on cell and tissue function. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
Topics: Animals; Collagen; Disease Models, Animal; Extracellular Matrix; Humans; Phenotype; Thrombospondins; Tissue Engineering
PubMed: 24440155
DOI: 10.1016/j.bbagen.2014.01.013 -
The Journal of Investigative... Dec 2000In order to grow beyond minimal size and to metastasize, tumors need to induce the growth of new blood vessels (angiogenesis). Whereas in normal tissues, vascular... (Review)
Review
In order to grow beyond minimal size and to metastasize, tumors need to induce the growth of new blood vessels (angiogenesis). Whereas in normal tissues, vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli, tumor angiogenesis is induced by increased secretion of angiogenic factors and/or by downregulation of angiogenesis inhibitors. Recent evidence suggests vascular endothelial growth factor (VEGF) as the major tumor angiogenesis factor, promoting tumor growth, invasion, and metastasis. Conversely, blocking of VEGF function inhibits angiogenesis and suppresses tumor growth in vivo. Newly identified members of the VEGF family of angiogenesis factors include placental growth factor, VEGF-B, VEGF-C, and VEGF-D, and show overlapping binding patterns to specific endothelial cell receptors. VEGF-C appears to play a major role as a lymphangiogenesis factor and as a growth factor for Kaposi's sarcoma. In contrast, endogenous inhibitors prevent blood vessel growth in normal tissues. In particular, thrombospondin-1 (TSP-1) and TSP-2 are expressed in normal skin and, when introduced into squamous cell carcinomas, potently inhibit malignant tumor growth via inhibition of tumor angiogenesis.
Topics: Animals; Endothelial Growth Factors; Humans; Lymphokines; Neovascularization, Pathologic; Skin Neoplasms; Thrombospondin 1; Thrombospondins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 11147670
DOI: 10.1046/j.1087-0024.2000.00003.x -
Turkish Neurosurgery 2021To measure serum levels of thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) in patients with common brain tumors, namely high-grade glioma (HGG), low-grade glioma...
AIM
To measure serum levels of thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) in patients with common brain tumors, namely high-grade glioma (HGG), low-grade glioma (LGG), and meningioma.
MATERIAL AND METHODS
For this prospective study, a total of 56 patients were operated on for supratentorial gliomas and meningiomas, and 18 healthy subjects were evaluated. Serum levels of angiostatic molecules were measured with enzyme-linked immunosorbent assay. The results of patients were compared with those of healthy subjects.
RESULTS
High serum levels of TSP-1 were seen in HGG, followed by LGG, meningioma groups, and controls. The only significant difference was found between HGGs and controls (p=0.004). There was a trend to decrease from HGG to controls. High serum levels of TSP-2 were seen in controls, followed by meningioma, LGG, and HGG. None of the patient groups showed significant differences compared with controls. Among the patient groups, TSP-2 was significantly higher in the meningioma group than the HGG group (p=0.01). No correlation was found with any of the molecules and the clinical parameters, including the presence of peritumoral edema or seizure, the anterior-posterior diameter of the tumor, and, more importantly, the grade of glioma.
CONCLUSION
Our results indicate that TSP-2 might be more important than TSP-1 in preventing angiogenesis and a major angiostatic factor in glioma cells.
Topics: Adult; Aged; Brain Neoplasms; Female; Glioma; Humans; Male; Meningeal Neoplasms; Meningioma; Middle Aged; Prospective Studies; Thrombospondin 1; Thrombospondins
PubMed: 33759165
DOI: 10.5137/1019-5149.JTN.28624-20.3 -
Journal of the American Society of... Sep 2017The phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major autoantigens in primary membranous nephropathy (MN), and... (Review)
Review
The phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major autoantigens in primary membranous nephropathy (MN), and define two molecular subclasses of this disease. Both proteins are large transmembrane glycoproteins expressed by the podocyte, and both induce IgG4-predominant humoral immune responses that produce circulating autoantibodies that can be used clinically for diagnostic and monitoring purposes. The biologic roles of these proteins remain speculative, although several features of THSD7A suggest a role in adhesion. PLA2R-associated MN was initially found to associate with risk alleles within , but subsequent studies have shifted the focus to the HLA-DRB locus. Three distinct humoral epitope-containing regions have been defined within the extracellular portion of PLA2R, and it appears that the number of targeted epitopes may determine disease severity. Although similar information is not yet available for THSD7A-associated MN, this form of MN may have a unique association with malignancy. Finally, it appears likely that other autoantigens in primary MN exist. Although protocols similar to those that identified PLA2R and THSD7A may be successful in the identification of novel antigenic targets in MN, newer techniques such as laser-capture mass spectrometry or protein arrays may be helpful as well.
Topics: Autoantibodies; Autoantigens; Epitopes; Glomerulonephritis, Membranous; HLA-DQ alpha-Chains; HLA-DR beta-Chains; Humans; Immunoglobulin G; Neoplasms; Podocytes; Receptors, Phospholipase A2; Thrombospondins
PubMed: 28674044
DOI: 10.1681/ASN.2017020178 -
Nature Metabolism Jan 2022Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo...
Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142 cells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Computational Biology; Gene Expression Profiling; Gene Expression Regulation; Genetic Heterogeneity; Humans; Immunophenotyping; Insulin Resistance; Metabolic Networks and Pathways; Mice; Obesity; RNA-Seq; Receptors, G-Protein-Coupled; Recombinant Proteins; Stem Cells; Thrombospondins
PubMed: 35027768
DOI: 10.1038/s42255-021-00509-1 -
Biochemical Pharmacology Jun 2019A Disintegrin and Metalloproteinase (ADAM) is a family of proteolytic enzymes that possess sheddase function and regulate shedding of membrane-bound proteins, growth... (Review)
Review
A Disintegrin and Metalloproteinase (ADAM) is a family of proteolytic enzymes that possess sheddase function and regulate shedding of membrane-bound proteins, growth factors, cytokines, ligands and receptors. Typically, ADAMs have a pro-domain, and a metalloproteinase, disintegrin, cysteine-rich and a characteristic transmembrane domain. Most ADAMs are activated by proprotein convertases, but can also be regulated by G-protein coupled receptor agonists, Ca ionophores and protein kinase C activators. A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) is a family of secreted enzymes closely related to ADAMs. Like ADAMs, ADAMTS members have a pro-domain, and a metalloproteinase, disintegrin, and cysteine-rich domain, but they lack a transmembrane domain and instead have characteristic thrombospondin motifs. Activated ADAMs perform several functions and participate in multiple cardiovascular processes including vascular smooth muscle cell proliferation and migration, angiogenesis, vascular cell apoptosis, cell survival, tissue repair, and wound healing. ADAMs may also be involved in pathological conditions and cardiovascular diseases such as atherosclerosis, hypertension, aneurysm, coronary artery disease, myocardial infarction and heart failure. Like ADAMs, ADAMTS have a wide-spectrum role in vascular biology and cardiovascular pathophysiology. ADAMs and ADAMTS activity is naturally controlled by endogenous inhibitors such as tissue inhibitors of metalloproteinases (TIMPs), and their activity can also be suppressed by synthetic small molecule inhibitors. ADAMs and ADAMTS can serve as important diagnostic biomarkers and potential therapeutic targets for cardiovascular disorders. Natural and synthetic inhibitors of ADAMs and ADAMTS could be potential therapeutic tools for the management of cardiovascular diseases.
Topics: ADAM Proteins; Amino Acid Motifs; Animals; Disintegrins; Endothelium, Vascular; Humans; Matrix Metalloproteinase Inhibitors; Thrombospondins; Vascular Diseases
PubMed: 30905657
DOI: 10.1016/j.bcp.2019.03.033 -
Turkish Neurosurgery 2021To measure the serum levels of strong angiostatic and synaptogenetic molecules thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) in patients with temporal lobe...
AIM
To measure the serum levels of strong angiostatic and synaptogenetic molecules thrombospondin-1 (TSP-1) and thrombospondin-2 (TSP-2) in patients with temporal lobe epilepsy (TLE) before and after surgery.
MATERIAL AND METHODS
In this prospective study, 20 patients operated for TLE and 20 healthy subjects were included. Serum levels of TSP-1 and TSP-2 were measured using enzyme-linked immunosorbent assay (ELISA).
RESULTS
Our findings showed that both groups had higher serum levels of both molecules "before" surgery than 10 days ?after?
SURGERY
However, a significant difference was noted between ?before? and "after" surgery regarding TSP-1 (p=0.00001). Although a marked decrease was found "after" surgery with respect to TSP-2, the difference did not reach statistical significance (p=0.22). In patients with TLE, serum levels of both molecules ?before? surgery were found to be significantly higher than in healthy controls (TSP-1, p=0.00001; TSP-2, p=0.007).
CONCLUSION
Serum levels of TSP-1 and TSP-2 are determined to be higher in patients with TLE than in healthy subjects, and the resection of epileptogenic tissues decreases the serum levels of these molecules. Future studies should involve a higher number of patients with serial serum levels of TSP-1 and TSP-2 at the long-term follow-up to correlate with seizure outcome.
Topics: Adult; Anterior Temporal Lobectomy; Biomarkers; Epilepsy, Temporal Lobe; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prospective Studies; Thrombospondin 1; Thrombospondins; Young Adult
PubMed: 33372257
DOI: 10.5137/1019-5149.JTN.29081-20.4 -
Hypertension (Dallas, Tex. : 1979) Jul 2022Aortic aneurysm is a complex pathology that can be lethal if not detected in time. Although several molecular mechanisms and pathways have been identified to be involved... (Review)
Review
Aortic aneurysm is a complex pathology that can be lethal if not detected in time. Although several molecular mechanisms and pathways have been identified to be involved in aortic aneurysm development and growth, the current lack of an effective pharmacological treatment highlights the need for a more thorough understanding of the factors that regulate the remodeling of the aortic wall in response to triggers that lead to aneurysm formation. This task is further complicated by the regional heterogeneity of the aorta and that thoracic and abdominal aortic aneurysm are distinct pathologies with different risk factors and distinct course of progression. ADAMs (a disintegrin and metalloproteinases) and ADAMTS (ADAMs with a thrombospondin motif) are proteinases that share similarities with other proteinases but possess unique and diverse properties that place them in a category of their own. In this review, we discuss what is known on how ADAMs and ADAMTSs are altered in abdominal aortic aneurysm and thoracic aortic aneurysm in patients, in different animal models, and their role in regulating the function of different vascular and inflammatory cell types. A full understanding of the role of ADAMs and ADAMTSs in aortic aneurysm will help reveal a more complete understanding of the underlying mechanism driving aneurysm formation, which will help towards developing an effective treatment in preventing or limiting the growth of aortic aneurysm.
Topics: ADAM Proteins; Animals; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Disintegrins; Humans; Thrombospondins
PubMed: 35543145
DOI: 10.1161/HYPERTENSIONAHA.122.17963 -
International Journal of Molecular... Jul 2017Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain... (Review)
Review
Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, and TSP4 are the most studied and functionally tested. TSP1 possesses anti-angiogenic activity and is able to activate transforming growth factor (TGF)-β, a potent profibrotic and anti-inflammatory factor. Both TSP2 and TSP4 are implicated in the control of ECM composition in hypertrophic hearts. TSP1, TSP2, and TSP4 also influence cardiac remodeling by affecting collagen production, activity of matrix metalloproteinases and TGF-β signaling, myofibroblast differentiation, cardiomyocyte apoptosis, and stretch-mediated enhancement of myocardial contraction. The development and evaluation of TSP-deficient animal models provided an option to assess the contribution of TSPs to cardiovascular pathology such as (myocardial infarction) MI, cardiac hypertrophy, heart failure, atherosclerosis, and aortic valve stenosis. Targeting of TSPs has a significant therapeutic value for treatment of cardiovascular disease. The activation of cardiac TSP signaling in stress and pressure overload may be therefore beneficial.
Topics: Apoptosis; Cardiovascular Diseases; Cell Differentiation; Collagen; Extracellular Matrix; Humans; Myocytes, Cardiac; Myofibroblasts; Protein Conformation; Thrombospondins
PubMed: 28714932
DOI: 10.3390/ijms18071540