Editorial [Hot topic: Thrombospondins (Guest Editor: Jack Lawler)]

During tissue development and remodeling, cells obtain informational cues from the proteins that comprise the extracellular matrix. The thrombospondins are a family of extracellular, calcium-binding proteins that modulate cellular proliferation, migration and differentiation. At least one of the five members of this gene family is expressed in virtually every tissue of the body. The thrombospondins participate in embryonic development, axon guidance, synaptogenesis, wound healing, and angiogenesis. They are up-regulated and function in various disease states including, diabetes, atherosclerosis, scleroderma and tumor progression. The importance of the thrombospondins in tissue remodeling is underscored by the observations that mice that lack thrombospondin-1 (TSP-1) or -2 have significant abnormalities in response to a wide range of challenges. In addition, mutations in cartilage oligomeric matrix protein (COMP or TSP-5) cause the human dwarfing conditions pseudoachondroplasia and multiple epiphyseal dysplasia. The reviews in this series focus on the importance of thrombospondins in various disease states and discuss potential ways that the knowledge that has been gained to date may be used to diagnose and treat disease. Recently, thrombospondin-1 has been shown to regulate thrombosis by inhibiting the degradation of high molecular weight von Willebrand factor. The review by Drs. Bonnefoy and Hoelerts in this series describes the effect of TSP-1 on von Willebrand factor function. TSP-1 binds to von Willebrand factor and protects it from degradation by ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin-1 repeat 13). In the absence of TSP-1, there is a decrease in the formation of the long strands of von Willebrand factor that support thombosis. TSP-1 also profoundly affects the cardiovascular system through the suppression of nitric oxide (NO). The review by Dr. Isenberg and colleagues describes the molecular basis for the inhibition of NO signaling by TSP-1, CD47 and CD36. TSP-1 limits NO function in endothelial cells, smooth muscle cells and platelets. The authors point out that therapeutic strategies that target TSP-1 and/or CD47 would enhance the beneficial effects of NO on blood flow and vascular remodeling. The TSP-1/CD47 axis has also been shown to be involved in the regulation of the immune response. The review by Dr. Sarfati and colleagues explains how the interaction of TSP-1 with CD47 suppresses dendritic and T cell function. This interaction contributes to the maintenance of peripheral tolerance and the cross talk between antigen presenting cells and T cells. In adult tissue, the inhibition of angiogenesis in the tumor microenvironment has received significant attention. The review by Dr. Volpert and coworkers describes the molecular mechanisms that underlie the inhibition of angiogenesis by TSP-1, with particular focus on the induction of apoptosis. Like most anti-angiogenic therapies, TSP-1-based therapies are well tolerated and have limited activity as a monotherapy. The review by Dr. Volpert and colleagues discusses the importance of developing strategies for the use of TSP-1-based combination therapies. The thrombospondins regulate tissue genesis and remodeling by modulating the structure of the extracellular matrix and cellular behavior. They exert their effect on the extracellular matrix in several ways. Through the activation of transforming growth factor (TGF) β, TSP-1 can affect the composition of the extracellular matrix. TSPs bind directly to other matrix proteins including laminin, collagens, fibronectin and fibrinogen. The inclusion of TSP-1 into fibrin preparations decreases the fibril thickness. The absence of TSP-2 results in abnormal collagen fibril assembly in the skin. TSPs also modulate extracellular matrix structure by inhibiting proteinases, including elastase, cathepsin G, plasmin and urokinase. Proteases, in turn, may regulate TSP-1 function. The review by Dr. Iruela-Arispe describes the characterization of proteases that cleave TSP-1. The members of the ADAMTS family of extracellular proteases contain multiple copies of the type 1 repeats (TSRs). Proteolytic cleavage of the TSPs may have dramatic effects on the activity and bioavailability of specific regions of the proteins during tissue remodeling.