The impact of Smad3 loss of function on TGF-β signaling and radiation-induced capsular contracture.

[BACKGROUND] Capsular contracture remains a major problem following prosthetic breast implantation, especially in patients undergoing irradiation. Recent studies suggest that such radiation injuries are a cascading process of cytokine activation, with transforming growth factor (TGF)-β acting as the "master switch." Because TGF-β signals through phosphorylation of Smad3, a plausible approach to abate TGF-β-induced capsular contracture would be to interrupt Smad3 signaling. To test this hypothesis, capsular contracture formation in wild-type and Smad3 knockout mice was compared using micro-computed tomographic and histologic examination.

[METHODS] On day 0, 48 mice were implanted with bilateral silicone gel implants. Postoperatively, animals were imaged using live-scan micro-computed tomographic scanning. Animals in the radiation arm then received a 10-Gy directed radiation dose. On postoperative days 21, 28, 35, and 42, animals were imaged again. Histologic evaluation was performed at necropsy.

[RESULTS] Irradiated implants in the wild-type mice demonstrated shape and contour deformation on micro-computed tomographic scanning beginning on postoperative day 21 and progressing through day 42. Conversely, micro-computed tomographic scanning of irradiated implants in knockout mice demonstrated few changes from day 0 through day 42. Corresponding histologic specimens from wild-type mice demonstrated irregular capsules composed of disorganized collagen that became thicker from day 21 to day 42. Irradiated knockout specimen maintained thin capsules from day 21 through day 42.

[CONCLUSIONS] In this work, inhibiting TGF-β signaling led to a reduction in radiation-induced capsular contracture as measured by micro-computed tomographic and histologic evaluation. The results of this study suggest a promising target for the prevention of capsular contracture through the development of anti-Smad3/TGF-β-based therapies.