Disease relevance of Thbs2

• Fra1 Tg mice, as well as Thbs1(-/-) Thbs2(-/-) mice, which do not show osteosclerosis, exhibit an edge-to-edge bite phenotype associated with craniofacial dysmorphism [1].
• TSP1 was found in cartilage proper with diminished staining around chondrocytes undergoing differentiation and hypertrophy, whereas TSP2 was restricted to the matrix surrounding chondrocytes of the growth zone cartilage [2].
• Specifically, TSP2-null mice display improved healing with minimal scarring and form well-vascularized foreign body capsules [3].
• Altered extracellular matrix remodeling and angiogenesis in sponge granulomas of thrombospondin 2-null mice [3].
• TSP-1(-/-) had a significantly greater effect on induced corneal neovascularization than did TSP-2(-/-), with the opposite being the case in developmental iris angiogenesis (P < 0.01) [4].

High impact information on Thbs2

• While TSP-2 deficiency did not affect tumor differentiation or proliferation, tumor cell apoptosis was significantly reduced [5].
• These results reveal upregulation of an endogenous angiogenesis inhibitor during multi step tumorigenesis and identify enhanced stromal TSP-2 expression as a novel host anti-tumor defense mechanism [5].
• Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis [6].
• The basis for the unusual phenotype of the TSP2-null mouse could derive from the structural role that TSP2 might play in collagen fibrillogenesis in skin and tendon [6].
• In an attempt to determine the function of TSP2, we disrupted the Thbs2 gene by homologous recombination in embryonic stem cells, and generated TSP2-null mice by blastocyst injection and appropriate breeding of mutant animals [6].

Chemical compound and disease context of Thbs2

• Angiotensin II induced fatal cardiac rupture in 70% of TSP2 knockout mice, with cardiac failure in the surviving mice; this was not seen in wild-type mice [7].
• To investigate the biologic role of the potent angiogenesis inhibitor thrombospondin-2 (TSP-2) in the control of cutaneous inflammation, delayed-type hypersensitivity reactions were elicited in the ear skin of wild-type and TSP-2-deficient mice by topical sensitization and challenge with oxazolone [8].

Biological context of Thbs2

• Thbs2 is located on chromosome 17, band A3, whereas Thbs1 was found on chromosome 2, band F [9].
• The exon/intron organization of Thbs2 is highly conserved in comparison with Thbs1 in that exon size and the pattern of interruption of the reading frame by introns are preserved, but there is a marked divergence in coding sequence, primarily in the first 7 exons [9].
• Interestingly, TSP1 and TSP2 exhibited markedly different tissue- and stage-specific patterns of mRNA expression during mouse embryogenesis, implying that the two TSP molecules possess discrete functional properties important for development [10].
• Characterization of mouse thrombospondin 2 sequence and expression during cell growth and development [10].
• Based on their translated amino acid sequences, it seems likely that TSP1 and TSP2 will be found to have both common and unique properties and that the functional consequences of TSP production will reflect the ratio of the levels of these two related proteins [11].

Anatomical context of Thbs2

• In marked contrast to Thbs1, the Thbs2 gene is not induced by serum in NIH 3T3 cells; promoter sequences in the two genes are also very different [9].
• We found that expression of Thbs1 and Thbs2 was reduced in Fra1 Tg osteoblasts [1].
• In contrast, a more constant level of thrombospondin 1 mRNA was apparent in resident megakaryocytes of the liver, as well as in circulating megakaryocytes; neither thrombospondin 2 nor 3 was detected in these cells [12].
• The expression of thrombospondin 2 was confined principally to organized connective tissue that included pericardium, pleura, perichondrium, periosteum, meninges, ligaments, and reticular dermis [12].
• Thrombospondin 2 was also produced by differentiating skeletal myoblasts and by cells of the kidney and gut [12].

Associations of Thbs2 with chemical compounds

• In addition, homotrimeric TSP2 has a lower affinity for heparin than homotrimeric TSP1 [13].
• Degradation of TSP2 was slower in cultures of Chinese hamster ovary (CHO) cells lacking heparan sulfate proteoglycans than in wild type CHO cells or in cultures of 3T3 cells treated with heparitinase than in untreated 3T3 cells [14].
• In addition, the NH2-terminal domain of TSP3 differs markedly, both in sequence and in exon/intron structure, from that in TSP1 or TSP2 [15].
• After a 4-week implantation period, both types of PDMS elicited a similar FBR with a collagenous capsule in both TSP2-null and control mice [16].
• Consistent with this hypothesis, MKs take up recombinant TSP2 in an integrin-dependent manner when it is supplied in the culture medium [17].

Physical interactions of Thbs2

• TSP2 binds directly to Notch3 and Jagged1 [18].

Other interactions of Thbs2

• To define the molecular requirements for assembly of fascin spikes by thrombospondins, we developed a panel of recombinant protein units of TSP-1 and TSP-2; these were designed according to the domain boundaries and included matched monomeric and trimeric units [19].
• Using the corneal pocket assay we found that TSP-2 did not inhibit bFGF-induced angiogenesis in CD36 null mice [20].
• PSC were isolated by outgrowth from normal mouse pancreas and expression of TSP-1 and TSP-2 was evaluated after serum-activation [21].
• Consistent with this finding, there was a decrease in expression of collagen and osteocalcin RNA by TSP2-null MSCs on day 7 and increased osteopontin expression on day 7 and day 14 [22].
• More recently, TSP1, TSP2, and SPARC have also been implicated in the foreign body response, an unusual reaction to injury that occurs after the implantation of biomaterials [23].

Analytical, diagnostic and therapeutic context of Thbs2

• We compared the distributions of TSP1 and TSP2 in mouse embryos (day 10 and later) by immunohistochemistry [2].
• Western blotting showed that TSP2 was expressed in the cervix of mice on Days 14 and 18 of pregnancy but not on Day 10 or in the nonpregnant animal [24].
• Thus, TSP2-null mice provide an animal model to assist in the understanding of the molecular basis of spontaneous, premature softening of the uterine cervix [24].
• Morphologically, the TSP2-null and wild-type (WT) cell populations were similar and by flow cytometry contained equivalent numbers of CD44+, Mac1+, intercellular adhesion molecule-1 (ICAM-1+), and ScaI+ cells [22].
• Determination of TSP2 protein content by Western analysis and RNA levels by reverse-transcription polymerase chain reaction (RT-PCR) indicated that MSCs are the primary source of TSP2 in the marrow and secrete abundant TSP2 into culture medium [22].

References