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 by modulating cell-matrix interactions, rather than acting as an integral component of the matrix. Thus, the structurally abnormal collagen fibrils detected in skin appear to be the consequence of the defective adhesion demonstrated by dermal fibroblasts in culture that, in turn, result from increased 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 distinct abnormalities in fibroblast-collagen fibril interactions in TSP2-null tissue. The increased vascular density seen in skin of TSP2-null mice can be reproduced in a number of models of injury, including subcutaneous implantation of polyvinyl alcohol sponges and silicone rubber discs, and excisional skin wounds. Experiments are proposed to distinguish between a primarily endothelial cell versus an extracellular matrix origin for the increased angiogenesis in TSP2-null mice.
Bornstein
P
P
Department of Biochemistry, University of Washington, Seattle 98195, USA. bornsten@u.washington.edu
Kyriakides
T R
TR
Yang
Z
Z
Armstrong
L C
LC
Birk
D E
DE
D000818:Animals; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012867:Skin / Q000098:blood supply* / Q000378:metabolism*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D000099262:Thrombospondin 2
D003094:Collagen; D019699:Thrombospondins; D000099262:Thrombospondin 2