Thrombospondin 2 modulates collagen fibrillogenesis and angiogenesis

Thrombospondin 2 (TSP2)-null mice, generated by targeted disruption of the Thbs2 gene, display a complex phenotype that is characterized, in part, by a variety of connective tissue abnormalities and increased vascular density in skin and subcutaneous tissues. In this paper we summarize the evidence that TSP2 functions as a matricellular protein to influence cell function b y modulating cell-matrix interactions, rather than acting as an integral co mponent of the matrix. Thus, the structurally abnormal collagen fibrils det ected in skin appear to be the consequence of the defective adhesion demons trated by dermal fibroblasts in culture that, in turn, result from increase d matrix metalloproteinase 2 (MMP2, gelatinase A) production by these cells . Corroborating evidence for such a mode of action comes from transmission electron microscopic images of developing flexor muscle tendons that show d istinct abnormalities in fibroblast-collagen fibril interactions in TSP2-nu ll tissue. The increased vascular density seen in skin of TSP2-null mice ca n be reproduced in a number of models of injury, including subcutaneous imp lantation of polyvinyl alcohol sponges and silicone rubber discs, and excis ional skin wounds. Experiments are proposed to distinguish between a primar ily endothelial cell versus an extracellular matrix origin for the increase d angiogenesis in TSP2-null mice.