Disease relevance of THBS

• Thrombospondin-1 (TSP-1), an acute phase reactant implicated in vascular disease, is a matricellular glycoprotein with six domains that confer different functions [1].
• Thrombospondin expression in aldosterone-producing adenomas [2].
• The effect of a monoclonal antibody to thrombospondin on the recovery of endothelial cells from hyperthermia as it relates to cytoskeletal organization and cell spreading was assessed [3].
• INTRODUCTION: Thrombospondin-1 (TSP-1), an extracellular matrix (ECM) glycoprotein, is associated with a variety of cellular processes relevant to atherosclerosis and intimal hyperplasia, including vascular smooth muscle cell (VSMC) migration [4].
• We report here that hypoxia induces TSP-1 gene and protein expression [5].

High impact information on THBS

• Thrombospondin causes activation of latent transforming growth factor-beta secreted by endothelial cells by a novel mechanism [6].
• The RGD sequence is located in the type 3 repeat region of TSP that has multiple Ca2+ binding sites and is subject to a complex intramolecular thiol-disulfide isomerization [7].
• Thrombospondin (TSP) contains the Arg-Gly-Asp (RGD) sequence that is thought to be important for cell adhesion mediated by several cell-surface integrin receptors [7].
• Lower DTT concentrations were required for enhancement of the adhesive activity of TSP if Ca2+ was chelated with EDTA [7].
• Disulfides modulate RGD-inhibitable cell adhesive activity of thrombospondin [7].

Chemical compound and disease context of THBS

• The effects of hypoxia both on the stabilization of the TSP-1 transcript and the stimulation of TSP-1 protein production are completely inhibited by arginine butyrate [5].
• The TSP-1 induction by hypoxia is a graded and reversible physiologic response and can be mimicked by the use of cobalt chloride or the inhibition of nitric oxide production, suggesting both the involvement of a heme-containing oxygen sensor and a role for the endogenous production of nitric oxide in TSP-1 regulation [5].

Biological context of THBS

• In contrast with TSP, VEGF expression increased during growth and development of the follicle [8].
• The molecular structure of corticotropin-induced secreted protein, a novel member of the thrombospondin family [9].
• Using both transwell and Dunn chamber assays, we demonstrate that TSP1 and hep I gradients stimulate endothelial cell chemotaxis [10].
• Since cell adhesion dynamics affect cell motility, we asked whether TSP1/hep I-induced intermediate adhesion alters cell migration [10].
• Thus, TSP1/hep I stimulation of intermediate adhesion regulates the migratory phenotype of endothelial cells and fibroblasts, suggesting a role for TSP1 in remodeling responses [10].

Anatomical context of THBS

• This observation suggests that these two members of the thrombospondin family exert distinct biological functions in the adrenal cortex [11].
• TSP colocalized with CD36 on granulosa cells (GC) in the follicle and in cultured cells [8].
• Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development [8].
• Treatment with focal adhesion-labilizing concentrations of TSP1/hep I in the absence of a gradient enhances endothelial cell random migration, or chemokinesis, associated with an increase in cells migrating, migration speed, and total cellular displacement [10].
• The matricellular extracellular matrix protein thrombospondin-1 (TSP1) stimulates focal adhesion disassembly through a sequence (known as the hep I peptide) in its heparin-binding domain [10].

Associations of THBS with chemical compounds

• Using a microchemotaxis chamber, VSMCs pre-incubated in SFM, DMSO (vehicle control), PD98059 (10 microM), or SB202190 (10 microM) were exposed to each domain, TSP-1, or SFM [1].
• The structure and the mechanical properties of fibrin clots are influenced by various macromolecules (i.e., hyaluronic acid and thrombospondin) and also by pH, ionic strength, and thrombin concentrations of the milieu in which they polymerize [12].
• Thrombospondin, a high molecular weight glycoprotein secreted by platelets in response to activation by thrombin, has been identified by immunofluorescence in bovine aortic endothelial cells, human foreskin fibroblasts, and human aortic smooth muscle cells [13].
• The inhibition of chemotaxis and spreading by antibodies against the beta 3 but not the beta 1 chain of the integrin receptor points to a role for the integrins in the interaction of endothelial cells with TSP [14].
• The interaction of the heparin-binding domain of TSP with cell-associated heparan sulfate appears to be an important mechanistic component for this activity of TSP [15].

Physical interactions of THBS

• A binding assay was used to determine the specificity of TSP-1 binding to MMP2 [4].
• We have previously shown that both heparin and fibronectin have two binding sites on the TSP-1 subunit which may require conformational change for their occupancy (R. Dardik and J. Lahav, 1987, Eur. J. Biochem. 168, 347; ibid 1989, 185, 581) [16].

Regulatory relationships of THBS

• CONCLUSION: TSP-1 induced MMP2 activation through transcriptional and posttranslational mechanisms [4].
• In addition, we correlated this biphasic effect on tube formation with the capacity of TSP-1 to stimulate the activity of a matrix metalloproteinase-9 (MMP-9) in BAE cell collagen gel cultures [17].

Other interactions of THBS

• CISP differs greatly, however, from TSP1 by the inducibility of its synthesis by cAMP [9].
• Calreticulin-null and LRP-null fibroblasts do not migrate in response to TSP1/hep I, nor do endothelial cells treated with the LRP inhibitor receptor-associated protein (RAP) [10].
• Furthermore, TSP1/hep I-induced focal adhesion disassembly is associated with reduced chemotaxis to basic fibroblast growth factor (bFGF) but enhanced chemotaxis to acidic (a)FGF, suggesting differential modulation of growth factor-induced migration [10].
• We investigated the ability of thrombospondins (TSP1 and TSP2) to activate these latent forms of TGF beta [18].
• We hypothesized that TSP-1 modulates MMP2 activity in VSMCs and is critical for VSMC migration [4].

Analytical, diagnostic and therapeutic context of THBS

• The protein levels of TSP1 and CISP/TSP2 varied accordingly with their respective mRNA levels, as shown by immunoprecipitation and immunofluorescence experiments [11].
• Immunohistochemistry confirmed the granulosa layer as the primary area within the follicle involved in TSP generation and that small follicles had the highest proportion of immunopositive cells [8].
• Immunoprecipitation with specific antiserum indicates that the 180,000-mol wt polypeptide is thrombospondin [19].
• A sensitive quantitative enzyme-linked immunosorbent assay (ELISA) was developed and used to determine that the accumulation of secreted thrombospondin was similar for endothelial cells and fibroblasts but was higher for smooth muscle cells [13].
• Cyanogen bromide fragments of the A alpha- and B beta-fibrinogen chains, resolved by gel filtration and reversed-phase chromatography, were examined for thrombospondin binding activity [20].

References