The thrombospondins are a family of extracellular calcium-binding proteins that modulate cellular phenotype. Thrombospondin-1 (TSP-1) reportedly regulates cellular attachment, proliferation, migration, and differentiation in vitro. To explore its function in vivo, we have disrupted the TSP-1 gene by homologous recombination in the mouse genome. Platelets from these mice are completely deficient in TSP-1 protein; however, thrombin-induced platelet aggregation is not diminished. TSP-1-deficient mice display a mild and variable lordotic curvature of the spine that is apparent from birth. These mice also display an increase in the number of circulating white blood cells, with monocytes and eosinophils having the largest percent increases. The brain, heart, kidney, spleen, stomach, intestines, aorta, and liver of TSP-1-deficient mice showed no major abnormalities. However, consistent with high levels of expression of TSP-1 in lung, we observe abnormalities in the lungs of mice that lack the protein. Although normal at birth, histopathological analysis of lungs from 4-wk-old TSP-1-deficient mice reveals extensive acute and organizing pneumonia, with neutrophils and macrophages. The macrophages stain for hemosiderin, indicating that diffuse alveolar hemorrhage is occurring. At later times, the number of neutrophils decreases and a striking increase in the number of hemosiderin-containing macrophages is observed associated with multiple-lineage epithelial hyperplasia and the deposition of collagen and elastin. A thickening and ruffling of the epithelium of the airways results from increasing cell proliferation in TSP-1-deficient mice. These results indicate that TSP-1 is involved in normal lung homeostasis.
Thrombospondin-1 (TSP-1) contains three type 1 repeats (TSRs), which mediate cell attachment, glycosaminoglycan binding, inhibition of angiogenesis, activation of TGFβ, and inhibition of matrix metalloproteinases. The crystal structure of the TSRs reported in this article reveals a novel, antiparallel, three-stranded fold that consists of alternating stacked layers of tryptophan and arginine residues from respective strands, capped by disulfide bonds on each end. The front face of the TSR contains a right-handed spiral, positively charged groove that might be the “recognition” face, mediating interactions with various ligands. This is the first high-resolution crystal structure of a TSR domain that provides a prototypic architecture for structural and functional exploration of the diverse members of the TSR superfamily.
AUTHOR CONTRIBUTIONS G.F., A.A. and A.L. performed experiments and helped analyze all data with supervision from R.K.J. and M.G.V.H. D.P.K., D.B. and D.F. contributed in identifying metabolic signatures of brain metastasis; K.LA. and A.W. contributed to in vitro work and GCMS analysis. A.D. and C.B.C. performed LCMS lipidomics and helped with analysis; L.B., B.P. and V.A.D performed IMS imaging and analysis; X.J. and T.R.G. contributed to extracellular fluid isolation and provided input on data interpretation. J.M.P., N.I.L. and E.B. collected clinical samples and contributed to analysis of patient tumor sections; J.C. and D.G.D. performed ultrasound imaging of liver tumors; C.R.C. and S.M.D. contributed to in vivo glucose tracing studies. Z.A. performed flow cytometry analysis. R.F. and J.N. helped with analysis of lipidomics data. I.C., C.N. and D.E.H. analyzed human expression databases. K.N. performed analysis of Affymetrix array. M.D. and S.R. contributed to CRISPR Cas9 methodology and animal implantations.
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