Interference with transforming growth factor-beta/ Smad3 signaling results in accelerated healing of wounds in previously irradiated skin.
Transforming growth factor (TGF)-beta regulates many aspects of wound repair including inflammation, chemotaxis, and deposition of extracellular matrix. We previously showed that epithelialization of incisional wounds is accelerated in mice null for Smad3, a key cytoplasmic mediator of TGF-beta signaling. Here, we investigated the effects of loss of Smad3 on healing of wounds in skin previously exposed to ionizing radiation, in which scarring fibrosis complicates healing. Cutaneous wounds made in Smad3-null mice 6 weeks after irradiation showed decreased wound widths, enhanced epithelialization, and reduced numbers of neutrophils and myofibroblasts compared to wounds in irradiated wild-type littermates. Differences in breaking strength of wild-type and Smad3-null wounds were not significant. As shown previously for neutrophils, chemotaxis of primary dermal fibroblasts to TGF-beta required Smad3, but differentiation of fibroblasts to myofibroblasts by TGF-beta was independent of Smad3. Previous irradiation-enhanced induction of connective tissue growth factor mRNA in wild-type, but not Smad3-null fibroblasts, suggested that this may contribute to the heightened scarring in irradiated wild-type skin as demonstrated by Picrosirius red staining. Overall, the data suggest that attenuation of Smad3 signaling might improve the healing of wounds in previously irradiated skin commensurate with an inhibition of fibrosis.
Flanders
Kathleen C
KC
Laboratory of Cell Regulation and Carcinogenesis and the Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 21201, USA.
Major
Christopher D
CD
Arabshahi
Alidad
A
Aburime
Ekinadese E
EE
Okada
Miya H
MH
Fujii
Makiko
M
Blalock
Timothy D
TD
Schultz
Gregory S
GS
Sowers
Anastasia
A
Anzano
Mario A
MA
Mitchell
James B
JB
Russo
Angelo
A
Roberts
Anita B
AB
D000818:Animals; D002921:Cicatrix / Q000209:etiology / Q000517:prevention & control; D055513:Connective Tissue Growth Factor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004848:Epithelium / Q000503:physiopathology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011832:Radiation Injuries / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D012867:Skin / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects*; D051900:Smad3 Protein; D013718:Tensile Strength; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014945:Wound Healing
C526318:CCN2 protein, mouse; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor