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Vol. 11, Issue 10, 3353-3364, October 2000
Departments of *Biochemistry and Thrombospondin 2 (TSP2)-null mice, generated by disruption of the
Thbs2 gene, display a variety of connective tissue
abnormalities, including fragile skin and the presence of abnormally
large collagen fibrils with irregular contours in skin and tendon. In
this study we demonstrate that TSP2-null skin fibroblasts show a defect
in attachment to a number of matrix proteins, and a reduction in cell
spreading. To investigate the molecular mechanisms responsible for
these abnormal cell-matrix interactions, we compared the levels of
matrix metalloproteinases (MMPs) in wild-type and mutant fibroblasts. Isolation and analysis of gelatinases from conditioned media by gelatin-agarose affinity chromatography and gelatinolytic assays demonstrated that TSP2-null fibroblasts produce a 2-fold increase in
gelatinase A (MMP2) compared with wild-type cells. The adhesive defect
was corrected by treatment of TSP2-null fibroblasts with soluble TSP2,
with the MMP inhibitors BB94 and tissue inhibitor of
metalloproteinase-2, and with a neutralizing antibody to MMP2. Moreover, stable transfection of TSP2-null fibroblasts with mouse TSP2
cDNA corrected both the adhesive defect and the altered expression of
MMP2. Finally, MMP2 was shown to interact with TSP2 in a direct-binding plate assay. We conclude that TSP2 plays an important role in cell-matrix interactions, and that a deficiency in the protein results
in increased levels of MMP2 that contribute to the adhesive defect in
TSP2-null fibroblasts and could play a role in the complex phenotype of
TSP2-null mice.
Medicine, University
of Washington, Seattle, Washington 98195
Corresponding author: E-mail
address: bornsten{at}u.washington.edu.
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