title: Activation of Latent TGF-β1 by Thrombospondin-1 is a Major Component of Wound Repair.
abstract: PURPOSE: Thrombospondin 1 (TSP1) is a matrix glycoprotein that regulates cell adhesion, migration, and proliferation, and is a natural inhibitor of angiogenesis. Recent evidence suggests that TSP1 is a major physiologic activator of latent transforming growth factor-β1 (TGF-β1), and that TGF-β1 is important for wound healing. The purpose of this study was to examine whether excisional wound healing in TSP1-deficient mice is compromised as a result of deficient TGF-β1 activation.  MATERIALS AND METHODS: Punch wounds were made on the dorsum of TSP1 deficient and wild-type mice and the area of granulation tissue, number of microvessels, and inflammatory cell infiltration was evaluated over a period of 28 days.  RESULTS: TSP1 deficient mice showed impaired wound healing with persistent granulation tissue, decreased collagen content over time, and delayed arrival of macrophages compared to wild-type littermates. The number of microvessels in wounds of TSP1-deficient mice was approximately two-fold greater than in wild-type littermates 10 days after injury. Topical application of TSP1, or KRFK (a peptide derived from TSP1 that activates latent TGF-β1), to wounds of TSP1-deficient mice rescued wild-type patterns of wound repair and partially recovered local levels of TGF-β1 expression. Topical application of anti-TGF-β neutralizing antibody impaired the ability of KRFK to rescue normal patterns of wound neovascularization in TSP1-deficient mice.  CONCLUSIONS: These results demonstrate that TSP1 plays a key role in the orchestration of wound healing, and that TSP1-mediated activation of local TGF-β1 is an important step in this process.
authors.affiliation: Angiogenesis Research Laboratory; Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, USA.
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nör
authors.forename: Luisa
authors.initials: L
authors.lastname: Dipietro
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Murphy-Ullrich
authors.forename: Richard O
authors.initials: RO
authors.lastname: Hynes
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Polverini