Exogenous transforming growth factor-beta(2) enhances connective tissue formation in transforming growth factor-beta(1)-deficient, healing-impaired dermal wounds in mice.
Connective tissue formation is markedly reduced in full-thickness mouse dermal wounds that are covered with synthetic, adherent, moisture vapor-permeable membrane when compared with formation in similar but nonoccluded wounds. The transforming growth factors-beta (TGF-beta) are a family of multifunctional peptides thought to have a critical role in the regulation of development and tissue repair. Treatment with exogenous TGF-beta(1) stimulated connective tissue formation in wounds covered with synthetic, adherent, moisture vapor-permeable membrane but had no effect on air-exposed wounds, suggesting that the quantity of endogenous TGF-beta(1) in wounds covered with synthetic, adherent, moisture vapor-permeable membrane was less than that in air-exposed wounds. Immunolocalization studies with an anti-TGF-beta(1) antibody confirmed that wounds covered with synthetic, adherent, moisture vapor-permeable membrane demonstrated markedly reduced levels of endogenous extracellular, matrix-associated TGF-beta(1) as early as 24 hours after wounding. Immunoreactive TGF-beta(2) was not detected. These findings suggest that endogenous TGF-beta(1), but not TGF-beta(2), is required for normal connective tissue formation in this model and that impaired healing is associated with low levels of TGF-beta(1). Histologic analysis confirmed previous demonstrations that exogenous TGF-beta(2) stimulates enhanced cellularity and connective tissue formation. Immunolocalization showed that exogenous TGF-beta(2) stimulates increased expression of endogenous TGF-beta(1). Northern blot analysis revealed that TGF-beta(2) increased the expression of genes encoding the alpha(1)-chain of types I and III collagens and tissue inhibitor of metalloproteinase-1. These observations show that TGF-beta(2) acts through a variety of mechanisms to stimulate repair in healing-impaired wounds that are also deficient in endogenous TGF-beta(1), but they do not distinguish between direct effects and indirect effects mediated by induced TGF-beta(1).
Ksander
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GA
Celtrix Pharmaceuticals, Inc., Santa Clara, California, USA.
Gerhardt
C O
CO
Olsen
D R
DR