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Journal of Orthopaedic Research :... Jan 2021Fracture healing is a complex process that relies heavily on the carefully orchestrated expansion and differentiation of periosteal mesenchymal progenitor cells (MSC)....
Fracture healing is a complex process that relies heavily on the carefully orchestrated expansion and differentiation of periosteal mesenchymal progenitor cells (MSC). Identification of new markers for periosteal MSCs is essential for the development of fracture therapeutics. Expression of the matricellular protein thrombospondin-2 (TSP2) increases during early fracture healing; however, it is currently unknown what cell population expresses TSP2. Using a TSP2 GFP reporter mouse and a stabilized murine fracture model, we characterized the expression of TSP2 during the inflammatory, soft callus formation, and hard callus formation phases of fracture healing. In addition, using TSP2 GFP positive cells harvested from reporter mouse cells, we characterized the cell population using flow cytometry and colony formation assays. In uninjured diaphyseal bone, we observed TSP2 expression in the cells located along the inner periosteum. We also observed a population of TSP2 expressing cells in undifferentiated regions of early fracture callus and along the periphery of the callus. Later in callus development, TSP2 cells were broadly distributed in the undifferentiated callus, but GFP was not expressed by chondrocytes. Flow cytometry confirmed that the majority of TSP2 expressing cells were positive for traditional murine MSC markers. Our in vitro assays further supported these findings by demonstrating all adherent and colony-forming cells expressed TSP2. Taken together, our results suggest that TSP2 is expressed by undifferentiated MSCs, but downregulated in chondrocytes. Clinical significance: expression of the matricellular protein TSP2 is a promising new marker to identify MSCs in early fracture healing.
Topics: Animals; Bony Callus; Cell Proliferation; Chondrocytes; Chondrogenesis; Fractures, Bone; Genes, Reporter; Mice; Thrombospondins
PubMed: 32437051
DOI: 10.1002/jor.24749 -
Technology and Health Care : Official... 2022Alveolar echinococcosis is an epidemic disease caused by the parasitism of Echinococcus multilocularis (Em) larvae in the intermediate or final host.
BACKGROUND
Alveolar echinococcosis is an epidemic disease caused by the parasitism of Echinococcus multilocularis (Em) larvae in the intermediate or final host.
OBJECTIVE
To identify and analyze B-cell and T-cell (Th1, Th2, and Th17) epitopes of the Em antigen protein thrombospondin 3 (TSP3).
METHODS
The amino acid sequence of TSP3 was obtained, and the secondary structural characteristics of TSP3 were predicted using bioinformatics software to further predict its potential T-cell and B-cell epitopes. The spleen lymphocytes of BALB/c mice, which were immunized with the TSP3 protein, were collected for co-culture with B-cell and T-cell antigen small peptides. The B-cell epitopes and T-cell epitope subtypes Th1, Th2, and Th17 were identified as having good immunogenicity.
RESULTS
After identification, it was found that the predominant epitopes of B cells existing in TSP3 were T18-33, T45-55, and T110-122. Furthermore, the predominant epitopes of T cells existing in TSP3 were T33-42, T45-55, T80-90, and T110-122 in the T1 subtype, T45-55, T68-77, and T92-104 in the Th2 subtype, and T53-63 and T80-90 in the Th17 subtype.
CONCLUSIONS
Six T-cell and eight B-cell dominant epitopes of the TSP3 antigen were revealed; these results may be applied in the development of a dominant epitope vaccine.
Topics: Animals; Echinococcosis; Echinococcus multilocularis; Epitopes, B-Lymphocyte; Mice; Thrombospondins
PubMed: 35068426
DOI: 10.3233/THC-212983 -
Frontiers in Bioscience (Landmark... Jan 2011The human ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family of 19 secreted, multidomain proteolytic enzymes is involved in a wide range... (Review)
Review
The human ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) family of 19 secreted, multidomain proteolytic enzymes is involved in a wide range of biological processes including ECM assembly and degradation, hemostasis, organogenesis and the regulation of angiogenesis. Defects in certain family members give rise to inherited human genetic diseases, while aberrant expression of other ADAMTSs has been linked to the pathogenesis of arthritis and cancer. Several ADAMTSs act as tumor or metastasis suppressors whose functions are lost either by mutation or epigenetic silencing during tumor progression. This review looks in depth at the involvement of ADAMTSs as positive and negative mediators in cancer growth and spread.
Topics: ADAM Proteins; Angiogenesis Inhibitors; Animals; Humans; Metalloproteases; Neoplasm Metastasis; Neoplasms; Thrombospondins
PubMed: 21196270
DOI: 10.2741/3827 -
The American Journal of Pathology Oct 2008Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known...
Radiation, a primary mode of cancer therapy, acutely damages cellular macromolecules and DNA and elicits stress responses that lead to cell death. The known cytoprotective activity of nitric oxide (NO) is blocked by thrombospondin-1, a potent antagonist of NO/cGMP signaling in ischemic soft tissues, suggesting that thrombospondin-1 signaling via its receptor CD47 could correspondingly increase radiosensitivity. We show here that soft tissues in thrombospondin-1-null mice are remarkably resistant to radiation injury. Twelve hours after 25-Gy hindlimb irradiation, thrombospondin-1-null mice showed significantly less cell death in both muscle and bone marrow. Two months after irradiation, skin and muscle units in null mice showed minimal histological evidence of radiation injury and near full retention of mitochondrial function. Additionally, both tissue perfusion and acute vascular responses to NO were preserved in irradiated thrombospondin-1-null hindlimbs. The role of thrombospondin-1 in radiosensitization is specific because thrombospondin-2-null mice were not protected. However, mice lacking CD47 showed radioresistance similar to thrombospondin-1-null mice. Both thrombospondin-1- and CD47-dependent radiosensitization is cell autonomous because vascular cells isolated from the respective null mice showed dramatically increased survival and improved proliferative capacity after irradiation in vitro. Therefore, thrombospondin-1/CD47 antagonists may have selective radioprotective activity for normal tissues.
Topics: Animals; Apoptosis; Blood Vessels; CD47 Antigen; Cell Proliferation; Cell Survival; Cells, Cultured; Endothelial Cells; Hindlimb; Hypertrophy; Male; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms; Radiation Injuries, Experimental; Radiation Tolerance; Thrombospondin 1; Thrombospondins; Tissue Survival; X-Rays
PubMed: 18787106
DOI: 10.2353/ajpath.2008.080237 -
Medicine Apr 2023The degeneration of articular cartilage tissue is the most common cause of articular cartilage diseases such as osteoarthritis. There are limitations in chondrocyte... (Review)
Review
The degeneration of articular cartilage tissue is the most common cause of articular cartilage diseases such as osteoarthritis. There are limitations in chondrocyte self-renewal and conventional treatments. During cartilage regeneration and repair, growth factors are typically used to induce cartilage differentiation in stem cells. The role of thrombospondin-2 in cartilage formation has received much attention in recent years. This paper reviews the role of thrombospondin-2 in cartilage regeneration and the important role it plays in protecting cartilage from damage caused by inflammation or trauma and in the regenerative repair of cartilage by binding to different receptors and activating different intracellular signaling pathways. These studies provide new ideas for cartilage repair in clinical settings.
Topics: Humans; Regeneration; Cartilage, Articular; Chondrocytes; Cartilage Diseases; Thrombospondins
PubMed: 37115081
DOI: 10.1097/MD.0000000000033651 -
Current Drug Targets Oct 2008The contribution of proteases to developmental, physiological and pathological processes has been well accepted. Cleavage of matrix proteins is a key requirement for... (Review)
Review
The contribution of proteases to developmental, physiological and pathological processes has been well accepted. Cleavage of matrix proteins is a key requirement for cell migration and remodeling of the extracellular environment. The constant process of matrix turnover is dependent on the delicate balance between degradation and synthesis. In addition, regulated proteolysis also allows for the release and activation of growth factors and cytokines. Similarly to other extracellular matrix proteins, thrombospondins are also targets of proteolysis. While in some cases enzymatic activity is associated with degradation of the protein; in other situations, targeted and selective cleavage offers the means to release polypeptides with either alternative or enhanced function. Here, we provide a summary of the published information related to thrombospondin proteolysis within the context of how proteolysis of extracellular matrix proteins impacts diversification of protein function. We also discuss its biological relevance and potential therapeutic value of thrombospondin proteolysis with particular emphasis on angiogenesis.
Topics: Animals; Extracellular Matrix Proteins; Humans; Peptide Hydrolases; Substrate Specificity; Thrombospondin 1
PubMed: 18855620
DOI: 10.2174/138945008785909365 -
Basic & Clinical Pharmacology &... Jan 2013The thrombospondin (TSP) family consists of five multimeric, multidomain calcium-binding glycoproteins that act as regulators of cell-cell and cell-matrix associations... (Review)
Review
The thrombospondin (TSP) family consists of five multimeric, multidomain calcium-binding glycoproteins that act as regulators of cell-cell and cell-matrix associations as well as interact with other extracellular matrix molecules affecting their function. Increasing interest on cardiac TSP-1, TSP-2 and TSP-4 has emerged, and they have been studied in cardiac hypertrophy, myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis. The aim of this MiniReview is to summarize the current knowledge on each TSP in various cardiovascular pathologies. We specifically emphasize the role of TSPs in cardiac remodelling and evaluate TSPs as potential cardiovascular drug targets. Thrombospondin-1 (TSP-1) is the most studied TSP, being antiangiogenic and able to activate transforming growth factor-β. The functions of TSP-2 and TSP-4 are linked in maintaining the composition of the matrix of the hypertrophied heart, whereas there is very little knowledge on cardiac TSP-3 and TSP-5. TSP-1, TSP-2 and TSP-4 have been shown to affect cardiac remodelling in vivo, for example, by modulating matrix metalloproteinase and transforming growth factor-β activity, collagen synthesis, myofibroblast differentiation, cell death and stretch-mediated augmentation of cardiac contractility. The detrimental role for TSPs in cardiovascular pathophysiology has been clearly demonstrated in knockout mouse models, and augmentation of TSP signalling in the heart during stress and haemodynamic overload might be beneficial. In conclusion, the role of TSP-1, TSP-2 and TSP-4 in cardiac hypertrophy, remodelling after myocardial infarction, heart failure, atherosclerosis and aortic valve stenosis encourages further investigation to validate them as potential drug targets.
Topics: Animals; Atherosclerosis; Calcinosis; Cardiovascular Diseases; Heart Failure; Heart Valve Diseases; Humans; Myocardial Infarction; Thrombospondins
PubMed: 23074998
DOI: 10.1111/bcpt.12026 -
Matrix Biology : Journal of the... Jul 2014Increasing evidence suggests critical functions of thrombospondins (TSPs) in a variety of physiological and pathological processes. With the growing understanding of the... (Review)
Review
Increasing evidence suggests critical functions of thrombospondins (TSPs) in a variety of physiological and pathological processes. With the growing understanding of the importance of these matricellular proteins, the need to understand the mechanisms of regulation of their expression and potential approaches to modulate their levels is also increasing. The regulation of TSP expression is multi-leveled, cell- and tissue-specific, and very precise. However, the knowledge of mechanisms modulating the levels of TSPs is fragmented and incomplete. This review discusses the known mechanisms of regulation of TSP levels and the gaps in our knowledge that prevent us from developing strategies to modulate the expression of these physiologically important proteins.
Topics: Alternative Splicing; Animals; Base Sequence; Embryo, Mammalian; Extracellular Matrix Proteins; Fibronectins; Gene Expression Regulation, Developmental; Humans; Mice; Molecular Sequence Data; Osteonectin; Protein Structure, Tertiary; Species Specificity; Tenascin; Thrombospondins
PubMed: 24582666
DOI: 10.1016/j.matbio.2014.02.001 -
Journal of Molecular and Cellular... Jan 2016The heart's reaction to ischemic injury from a myocardial infarction involves complex cross-talk between the extra-cellular matrix (ECM) and different cell types within... (Review)
Review
The heart's reaction to ischemic injury from a myocardial infarction involves complex cross-talk between the extra-cellular matrix (ECM) and different cell types within the myocardium. The ECM functions not only as a scaffold where myocytes beat synchronously, but an active signaling environment that regulates the important post-MI responses. The thrombospondins are matricellular proteins that modulate cell--ECM interactions, functioning as "sensors" that mediate outside-in and inside-out signaling. Thrombospondins are highly expressed during embryonic stages, and although their levels decrease during adult life, can be re-expressed in high quantities in response to cardiac stress including myocardial infarction and heart failure. Like a Swiss-army knife, the thrombospondins possess many tools: numerous binding domains that allow them to interact with other elements of the ECM, cell surface receptors, and signaling molecules. It is through these that the thrombospondins function. In the present review, we provide basic as well as clinical evidence linking the thrombospondin proteins with the post myocardial infarction response, including inflammation, fibrotic matrix remodeling, angiogenesis, as well as myocyte hypertrophy, apoptosis, and contractile dysfunction in heart failure. We will describe what is known regarding the intracellular signaling pathways that are involved with these responses, paving the road for future studies identifying these proteins as therapeutic targets for cardiac disease.
Topics: Animals; Apoptosis; Endomyocardial Fibrosis; Extracellular Matrix; Gene Expression Regulation; Heart Failure; Humans; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Neovascularization, Physiologic; Signal Transduction; Thrombospondins
PubMed: 26686988
DOI: 10.1016/j.yjmcc.2015.12.009 -
Advances in Pharmacology (San Diego,... 2022A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic...
A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are two closely related families of proteolytic enzymes. ADAMs are largely membrane-bound enzymes that act as molecular scissors or sheddases of membrane-bound proteins, growth factors, cytokines, receptors and ligands, whereas ADAMTS are mainly secreted enzymes. ADAMs have a pro-domain, and a metalloproteinase, disintegrin, cysteine-rich and transmembrane domain. Similarly, ADAMTS family members have a pro-domain, and a metalloproteinase, disintegrin, and cysteine-rich domain, but instead of a transmembrane domain they have thrombospondin motifs. Most ADAMs and ADAMTS are activated by pro-protein convertases, and can be regulated by G-protein coupled receptor agonists, Ca ionophores and protein kinase C. Activated ADAMs and ADAMTS participate in numerous vascular processes including angiogenesis, vascular smooth muscle cell proliferation and migration, vascular cell apoptosis, cell survival, tissue repair, and wound healing. ADAMs and ADAMTS also play a role in vascular malfunction and cardiovascular diseases such as hypertension, atherosclerosis, coronary artery disease, myocardial infarction, heart failure, peripheral artery disease, and vascular aneurysm. Decreased ADAMTS13 is involved in thrombotic thrombocytopenic purpura and microangiopathies. The activity of ADAMs and ADAMTS can be regulated by endogenous tissue inhibitors of metalloproteinases and other synthetic small molecule inhibitors. ADAMs and ADAMTS can be used as diagnostic biomarkers and molecular targets in cardiovascular disease, and modulators of ADAMs and ADAMTS activity may provide potential new approaches for the management of cardiovascular disorders.
Topics: ADAM Proteins; Cysteine; Disintegrins; Humans; Thrombospondins; Vascular Diseases
PubMed: 35659374
DOI: 10.1016/bs.apha.2021.11.002