Thrombospondin 1, thrombospondin 2 and the eye
ABSTRACT Thrombospondin 1 and thrombospondin 2 (TSP1 and TSP2), which comprise the subgroup A thrombospondins, are matricellular proteins. As matricellular proteins, they modulate interactions between cells and the cellular environment, regulate cell adhesion and typically are expressed during tissue formative processes. In general, TSP1 and TSP2 counter angiogenesis (including tumour angiogenesis) and play important but contrasting roles during cutaneous repair. The two proteins are involved in development, including that of the eye, although evidence suggests that they have their greatest impact during tissue production in the adult. In the normal adult eye, they tend to be found at sites of ongoing matrix synthesis or cell-matrix interactions. At these sites, the two proteins possibly influence cellular differentiation and/or basement membrane deposition. TSP1 is also present in the intraocular fluids and drainage pathway, where it may function in maintaining the anti-angiogenic environment and in intraocular pressure control, respectively. TSP1 could also be involved in ocular immune privilege. Unlike in skin wounds, where TSP1 is derived from the blood and is present only in the early phases of repair, ocular tissue damage appears to lead to protacted TSP1 synthesis by local cells. This response might help suppress angiogenesis in the transparent tissues of the eye and so lessen visual axis opacification following injury. However, TSP2, which is also produced by damaged ophthalmic tissue and may be especially important in matrix organisation, seems to augment contraction in anomalous intraocular fibrosis. Elucidating the roles of TSP1 and TSP2 in ocular physiology and pathobiology may lead to improved therapies for neovascular, neoplastic, reparative and other ophthalmic diseases.
- SourceAvailable from: John I Clark
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- "One of the down-regulated matrix genes, thrombospondin 2, is a member of the matricellular protein family found in the lens epithelium. Knocking out thrombospondin 2 in addition to SPARC potentiates the accelerated dermal wound healing response observed in single-null mice, indicating the importance of cell-matrix interactions (Hiscott et al., 2006; Puolakkainen et al., 2005). The relationship between SPARC and type I collagen was established by a previous report showing decreased dermal protein levels of type I collagen in SPARC-null mice (Bradshaw et al., 2003) and further confirmed by array studies showing decreased type I collagen expression in the SPARC-null lens. "
ABSTRACT: SPARC is a matricellular glycoprotein involved in regulation of extracellular matrix, growth factors, adhesion, and migration. SPARC-null mice have altered basement membranes and develop posterior sub-capsular cataracts with cell swelling and equatorial vacuoles. Exchange of fluid, nutrients, and waste products in the avascular lens is driven by a unique circulating ion current. In the absence of SPARC, increased circulation of fluid, ions, and small molecules led to increased fluorescein distribution in vivo, loss of resting membrane polarization, and altered distribution of small molecules. Microarray analysis of SPARC-null lenses showed changes in gene expression of ion channels and receptors, matrix and adhesion genes, cytoskeleton, immune response genes, and cell signaling molecules. Our results confirm the hypothesis that the regulation of SPARC on cell-capsular matrix interactions can increase the circulation of fluid and ions in the lens, and the phenotype in the SPARC-null mouse lens is the result of multiple intersecting functional pathways.Experimental Eye Research 05/2009; 89(3):416-25. DOI:10.1016/j.exer.2009.04.008 · 3.02 Impact Factor
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- "The five different forms of thrombospondins (TSP1-5) are divided into two subgroups according to their oligomerization properties and molecular architecture. Subgroup A (TSP-1 and -2) are members of the thrombospondin type1(TSP1) repeat supergene family which forms homotrimers and subgroup B (TSP-3, -4 and -5) forms homopentamers  . TSP-1 contains several distinct domains, including an N-terminal heparin binding domain (HBD), a procollagen region, three type I (properdin) repeats, three type 2 (epidermal growth factor-like) repeats, type 3 repeats (calcium binding), and a C-terminal domain . "
ABSTRACT: Interactions between Trypanosoma cruzi and the extracellular matrix play an important role in cellular invasion. Here we show that T. cruzi increases the levels of thrombospondin-1 (TSP-1) expression in host cells during early infection. Stable RNA interference of host cell TSP-1 knocks down the levels of TSP-1 transcripts and protein expression in mammalian cells causing inhibition of T. cruzi infection. Addition of TSP-1 to these cells restores infection. Thus, host TSP-1, regulated by the parasite, plays a crucial role in early infection. This is the first report showing that a human parasite modulates TSP-1 expression to facilitate infection.FEBS Letters 05/2006; 580(9):2365-70. DOI:10.1016/j.febslet.2006.03.054 · 3.34 Impact Factor
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ABSTRACT: Corneal angiogenesis is associated with a variety of corneal diseases, and is sometimes vision threatening. In recent years, with the discovery of major pro- and anti-angiogenic factors in the cornea, details of the angiogenic process are gradually unveiled. Of note, corneal inflammation and neovascularization associated with severe limbal stem cell (LSC) deficiency is a clinically challenging issue in that the condition persists long after the initial insult, and will not improve without transplantation of LSCs. However, to date the molecular mechanism by which LSC transplantation restores corneal avascularity is not fully understood. In addition to discussing major pro-angiogenic factors involved in corneal neovascularization, this review article also focuses on possible molecular mechanisms underlying persistent inflammation and neovascularization following severe LSC deficiency, and anti-angiogenic factors expressed by human limbo-corneal epithelial cells (HLCECs). Most of the recently discovered corneal anti-angiogenic factors belong to extracellular matrix proteins that acquire angio-inhibitory activity only after proper proteolytic processing. Our recent findings showed that the secretion of endostatin (derived from basement membrane collagen XVIII) and restin (from collagen XV) by HLCECs were enhanced when HLCECs were cultivated on amniotic membrane (AM). This adds to the advantage of transplanting ex vivo expanded HLCECs cultivated on AM in that the anti-angiogenic activity of the epithelial cells is augmented in a physiological way. Furthermore, proteomic profiling of HLCECs and human conjunctival epithelial cells (HCECs) identified a 14-3-3 protein (stratifin) preferentially expressed by HLCECs. In addition to functioning as a cell cycle controller, keratinocyte-derived stratifin induces MMPs which are involved in the generation of restin (by MMP-1) and endostatin (by MMP-3). These findings highlight the significance of delicate epithelial-matrix interactions in the maintenance of corneal avascularity.Progress in Retinal and Eye Research 12/2006; 25(6):563-90. DOI:10.1016/j.preteyeres.2006.09.001 · 9.90 Impact Factor