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© The Rockefeller University Press, 0021-9525/1998//419 $5.00
The Journal of Cell Biology, Volume 140, Number 2, , 1998 419-430

Article

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



Themis R. Kyriakides*, Yu-Hong Zhu*, Lynne T. Smith{ddagger}, Steven D. Bain§, Zhantao Yang*, Ming T. Lin*, Keith G. Danielson||, Renato V. Iozzo||, Mary LaMarca, Cindy E. McKinney, Edward I. Ginns, and Paul Bornstein*,{ddagger}

* Department of Biochemistry, {ddagger} Department of Medicine, University of Washington, Seattle, Washington 98195; § Zymogenetics, Inc., Seattle, Washington 98105; || Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and Clinical Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892

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.

Abbreviations used in this paper: EDS, Ehlers-Danlos syndrome; ES, embryonic stem; H&E, hematoxylin and eosin; LRP, lipoprotein-related receptor protein; pQCT, peripheral quantitative computer tomography; TSP, Thrombospondin; vWF, von Willebrand factor.

Address all correspondence to Paul Bornstein, Department of Biochemistry, Box 357350, University of Washington, Seattle, WA 98195. Tel.: (206) 543-1789. Fax: (206) 685-4426. E-mail: bornsten{at}u.washington.edu


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