THROMBOSPONDIN-1 IS A MAJOR ACTIVATOR OF TGF-BETA-1 IN-VIVO

The activity of TGF-beta 1 is regulated primarily extracellularly wher e the secreted latent form must be modified to expose the active molec ule. Here we show that thrombospondin-1 is responsible for a significa nt proportion of the activation of TGF-beta 1 in vivo. Histological ab normalities in young TGF-beta 1 null and thrombospondin-1 null mice we re strikingly similar in nine organ systems. Lung and pancreas patholo gies similar to those observed in TGF-beta 1 null animals could be ind uced in wild-type pups by systemic treatment with a peptide that block ed the activation of TGF-beta 1 by thrombospondin-1. Although these or gans produced little active TGF-beta 1 in thrombospondin null mice, wh en pups were treated with a peptide derived from thrombospondin-l that could activate TGF-beta 1, active cytokine was detected in situ, and the lung and pancreatic abnormalities reverted toward wild type.