Mice That Lack Thrombospondin 2 Display Connective Tissue Abnormalities That Are Associated with Disordered Collagen Fibrillogenesis, an Increased Vascular Density, and a Bleeding Diathesis

Abstract

Thrombospondin (TSP) 2, and its close relative TSP1, are extracellular proteins whose functions are complex, poorly understood, and controversial. 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. Thbs2−/− mice were produced with the expected Mendelian frequency, appeared overtly normal, and were fertile. However, on closer examination, these mice displayed a wide variety of abnormalities. Collagen fiber patterns in skin were disordered, and abnormally large fibrils with irregular contours were observed by electron microscopy in both skin and tendon. As a functional correlate of these findings, the skin was fragile and had reduced tensile strength, and the tail was unusually flexible. Mutant skin fibroblasts were defective in attachment to a substratum. An increase in total density and in cortical thickness of long bones was documented by histology and quantitative computer tomography. Mutant mice also manifested an abnormal bleeding time, and histologic surveys of mouse tissues, stained with an antibody to von Willebrand factor, showed a significant increase in blood vessels. 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. However, it seems likely that some of the diverse manifestations of this genetic disorder result from the ability of TSP2 to modulate the cell surface properties of mesenchymal cells, and thus, to affect cell functions such as adhesion and migration.

Genes for systemic vascular complications are differentially expressed in the livers of Type 2 diabetic patients

“…Mice deficient in thrombospondin 2 have a phenotype that could reduce the risk of myocardial infarction [27]. Thus the upregulation of thrombospondin 2 and down-regulation of paraoxonase in the diabetic liver, as observed in this study, might be associated with increased risk of coronary artery disease.…”

New insights into elastic fiber assembly

“…All of the phenotypes show variable penetrance with the exception of the bleeding diathesis, which is completely penetrant in all backgrounds, including C57Bl/6. The phenotypes observed in the BSw mfap22/2 mouse are similar to matricellular proteins that bind matrix proteins, but do not contribute to the structural integrity of the ECM, such as thrombospondin (Kyriakides et al, 1998) and secreted protein acidic and rich in cysteine (SPARC) (osteonectin) (Bradshaw et al, 2003).…”

Angiogenesis and development of adipose tissue

“…Despite its pleiotropic biological role, mice deficient in TSP-1 are viable and exhibit only subtle abnormalities in development, although they develop pneumonia and show delayed organization and neovascularization of skin wounds (Agah et al, 2002). In contrast, TSP-2 deficient mice display a pleiotropic phenotype that includes fragile skin, which is associated with abnormal collagen fibrillogenesis, increased vascularity primarily in reponse to injury, increased cortical bone density, and a bleeding diathesis (Kyriakides et al, 1998). Both TSP-1 and TSP-2 are found to be secreted by human adipose tissue (Alvarez-Llamas et al, 2007).…”