Oral Biosci Med 2 (2005), No. 4 27. Jan. 2006
Oral Biosci Med 2 (2005), No. 2-3 (30.08.2005)
Activation of Latent TGF-ß1 by Thromobospondin-1 is a Major Component of Wound Repair
Nör, Jacques E./DiPietro, Luisa/Murphy-Ullrich, Joanne E./Hynes, Richard O./Lawler, Jack/Polverini, Peter J.
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-ß1 (TGF-ß1), and that TGF-ß1 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-ß1 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-ß1), to wounds of TSP1-deficient mice rescued wildtype patterns of wound repair and partially recovered local levels of TGF-ß1 expression. Topical application of anti-TGF-ß 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-ß1 is an important step in this process.
Keywords: angiogenesis, neovascularization, oral cavity, apoptosis