Published online before print November 26, 2008

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(American Journal of Pathology. 2009;174:248-255.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080576

β-Catenin Is a Mediator of the Response of Fibroblasts to Irradiation

Ananta Gurung^*, Faisal Uddin^*, Richard P. Hill, Peter C. Ferguson^¶ and Benjamin A. Alman^*¶

From the Program in Developmental and Stem Cell Biology,^* Hospital for Sick Children, Toronto; the Department of Laboratory Medicine and Pathobiology, the Division of Orthopaedic Surgery,^¶ and the Ontario Cancer Institute, Princess Margaret Hospital and Department of Medical Biophysics, University of Toronto, Toronto; and The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada

Radiation causes soft tissue complications that include fibrosis and deficient wound healing. β-Catenin, a key component in the canonical Wnt-signaling pathway, is activated in fibrotic processes and wound repair and, as such, could play a role in mediating cellular responses to irradiation. β-Catenin can form a transcriptionally active complex with members of the Tcf family. A reporter mouse model, in addition to human cell cultures, was used to demonstrate that ionizing radiation activates β-catenin-mediated, Tcf-dependent transcription both in vitro and in vivo. Furthermore, radiation activates β-catenin via a Wnt-mediated mechanism, as in the presence of dickkopf-1, an inhibitor of Wnt receptor activation, β-catenin levels did not increase after irradiation. Fibroblast cell cultures were derived from mice expressing either null or stabilized β-catenin alleles. Cells expressing stabilized β-catenin alleles had a higher proliferation rate and formed more colony-forming units than wild-type or null cells after irradiation. Wound healing was studied in these same mice after irradiation. There was a positive correlation between the tensile strength of the wound, the expression levels of type 1 collagen in the skin, and β-catenin levels. Mice treated with lithium showed increased β-catenin levels and increased wound strength. β-Catenin mediates the effects of ionizing radiation in fibroblasts, and its modulation has the potential to decrease the severity of radiation-induced soft tissue complications.