title: The impact of Smad3 loss of function on TGF-β signaling and radiation-induced capsular contracture.
abstract: 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.
authors: Rochester, N.Y. From the Division of Plastic and Reconstructive Surgery, Department of General Surgery, the Center for Musculoskeletal Research, Department of Orthopedics, the Department of Radiation Oncology, and the Department of Biomedical Engineering, University of Rochester Medical Center.
authors: Evan B
authors: EB
authors: Katzel
authors: Peter F
authors: PF
authors: Koltz
authors: Ryan
authors: R
authors: Tierney
authors: Jacqueline P
authors: JP
authors: Williams
authors: Hani A
authors: HA
authors: Awad
authors: Regis J
authors: RJ
authors: O'Keefe
authors: Howard N
authors: HN
authors: Langstein
references: Adams WP Jr. Capsular contracture: What is it? What causes it? How can it be prevented and managed? Clin Plast Surg. 2009;36:119–126, vii.
references: Wiener TC. Relationship of incision choice to capsular contracture. Aesthetic Plast Surg. 2008;32:303–306.
references: Bastos EM, Neto MS, Alves MT, et al. Histologic analysis of zafirlukast's effect on capsule formation around silicone implants. Aesthetic Plast Surg. 2007;31:559–565.
references: D'Andrea F, Nicoletti GF, Grella E, et al. Modification of cysteinyl leukotriene receptor expression in capsular contracture: Preliminary results. Ann Plast Surg. 2007;58:212–214.
references: Del Pozo JL, Tran NV, Petty PM, et al. Pilot study of association of bacteria on breast implants with capsular contracture. J Clin Microbiol. 2009;47:1333–1337.
references: Rosato RM, Dowden RV. Radiation therapy as a cause of capsular contracture. Ann Plast Surg. 1994;32:342–345.
references: Spear SL, Onyewu C. Staged breast reconstruction with saline-filled implants in the irradiated breast: Recent trends and therapeutic implications. Plast Reconstr Surg. 2000;105:930–942.
references: Tallet AV, Salem N, Moutardier V, et al. Radiotherapy and immediate two-stage breast reconstruction with a tissue expander and implant: Complications and esthetic results. Int J Radiat Oncol Biol Phys. 2003;57:136–142.
references: Whitfield GA, Horan G, Irwin MS, Malata CM, Wishart GC, Wilson CB. Incidence of severe capsular contracture following implant-based immediate breast reconstruction with or without postoperative chest wall radiotherapy using 40 Gray in 15 fractions. Radiother Oncol. 2009;90:141–147.
references: Kronowitz SJ, Robb GL. Radiation therapy and breast reconstruction: A critical review of the literature. Plast Reconstr Surg. 2009;124:395–408.
references: Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: A master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys. 2000;47:277–290.
references: Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995;33:99–109.
references: Brown KA, Pietenpol JA, Moses HL. A tale of two proteins: Differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem. 2007;101:9–33.
references: Katzel EB, Koltz PF, Tierney R, et al. A novel animal model to study silicone gel related capsular contracture. Plast Reconstr Surg. 2010;126:1483–1491.
references: Roberts AB, Lamb LC, Newton DL, Sporn MB, De Larco JE, Todaro GJ. Transforming growth factors: Isolation of polypeptides from virally and chemically transformed cells by acid/ethanol extraction. Proc Natl Acad Sci USA. 1980;77:3494–3498.
references: Ashcroft GS, Yang X, Glick AB, et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol. 1999;1:260–266.
references: Ashcroft GS, Roberts AB. Loss of Smad3 modulates wound healing. Cytokine Growth Factor Rev. 2000;11:125–131.
references: Hakelius L, Ohlsén L. Tendency to capsular contracture around smooth and textured gel-filled silicone mammary implants: A five-year follow-up. Plast Reconstr Surg. 1997;100:1566–1569.
references: Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol. 2002;160:1057–1068.
references: Flanders KC, Major CD, Arabshahi A, et al. Interference with transforming growth factor-beta/Smad3 signaling results in accelerated healing of wounds in previously irradiated skin. Am J Pathol. 2003;163:2247–2257.
references: Awad HA, Zhang X, Reynolds DG, Guldberg RE, O'Keefe RJ, Schwarz EM. Recent advances in gene delivery for structural bone allografts. Tissue Eng. 2007;13:1973–1985.
references: Reynolds DG, Hock C, Shaikh S, et al. Micro-computed tomography prediction of biomechanical strength in murine structural bone grafts. J Biomech. 2007;40:3178–3186.
references: Katzel EB, Koltz P, Awad HA, O'Keefe RJ, Williams J, Langstein HN. A novel animal model to study capsular contracture utilizing livescan microCT technology. Plast Reconstr Surg. 2009;124:19–20.
references: Ravin AG, Olbrich KC, Levin LS, Usala AL, Klitzman B. Long- and short-term effects of biological hydrogels on capsule microvascular density around implants in rats. J Biomed Mater Res. 2001;58:313–318.
references: Ruiz-de-Erenchun R, Dotor de las Herrerías J, Hontanilla B. Use of the transforming growth factor-beta1 inhibitor peptide in periprosthetic capsular fibrosis: Experimental model with tetraglycerol dipalmitate. Plast Reconstr Surg. 2005;116:1370–1378.
references: Henriksen TF, Fryzek JP, Holmich LR, et al. Surgical intervention and capsular contracture after breast augmentation: A prospective study of risk factors. Ann Plast Surg. 2005;54:343–351.
references: Loiselle AE, Bragdon GA, Jacobson JA, et al. Remodeling of murine intrasynovial tendon adhesions following injury: MMP and neotendon gene expression. J Orthop Res. 2009;27:833–840.