Transforming Growth Factor-β3 Therapy Delays Postoperative Reossification and Improves Craniofacial Growth in Craniosynostotic Rabbits

Postoperative reossification is a common clinical correlate following surgery. It has been suggested that an underexpression of transforming growth factor-β3 (TGF-β3) may be related to craniosynostosis and postoperative reossification. Adding TGF-β3 may delay reossification and improve postoperative growth. The present study was designed to test this hypothesis. Thirty 10-day-old New Zealand white rabbits with hereditary coronal suture synostosis were divided into three groups: (1) suturectomy controls (n = 14), (2) suturectomy treated with bovine serum albumin (n = 8), and (3) suturectomy treated with TGF-β3 protein (n = 8). At 10 days of age, a 3-mm × 15-mm coronal suturectomy was performed, and serial three-dimensional (3D) computed tomography (CT) scans and cephalographs were taken at 10, 25, 42, and 84 days of age. Calvaria were harvested at 84 days of age for histomorphometric analysis. Mean differences were analyzed using a group by age analysis of variance. Analysis of the 3D CT scan data revealed that sites treated with TGF-β3 had significantly (P < .05) greater defect areas and significantly (P < .05) greater intracranial volumes through 84 days of age compared with controls. Histomorphometry showed that sites treated with TGF-β3 had patent suturectomy sites and significantly (P < .001) less new bone in the suturectomy site compared with controls. Serial radiograph data revealed significant (P < .05) differences in craniofacial growth from 25 to 84 days in TGF-β3-treated rabbits compared with controls. Data show that TGF-β3 administration delayed reossification and improved craniofacial growth in this rabbit model. These findings also suggest that this molecular-based therapy may have potential clinical use.

[1]  A. Moursi,et al.  Delivery of Transforming Growth Factor-β3 Plasmid in a Collagen Gel Inhibits Cranial Suture Fusion in Rats , 2013, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

[2]  A. Moursi,et al.  The development of molecular therapies for craniosynostosis , 2012 .

[3]  P. Taub,et al.  Pediatric Craniofacial Surgery: A Review for the Multidisciplinary Team , 2011, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

[4]  R. Keating,et al.  Long-Term Outcomes of Primary Craniofacial Reconstruction for Craniosynostosis: A 12-Year Experience , 2011, Plastic and reconstructive surgery.

[5]  C. Bettegowda,et al.  The evolution of surgical management for craniosynostosis , 2010 .

[6]  I. Pollack,et al.  A single-center experience with symptomatic postoperative calvarial growth restriction after extended strip craniectomy for sagittal craniosynostosis. , 2010, Journal of neurosurgery. Pediatrics.

[7]  J. Jayamohan,et al.  Reoperation for Intracranial Hypertension in TWIST1-Confirmed Saethre-Chotzen Syndrome: A 15-Year Review , 2009, Plastic and reconstructive surgery.

[8]  M. Longaker,et al.  Differential Effects of TGF-&bgr;1 and TGF-&bgr;3 on Chondrogenesis in Posterofrontal Cranial Suture–Derived Mesenchymal Cells In Vitro , 2009, Plastic and reconstructive surgery.

[9]  M. Cohen.  Perspectives on craniosynostosis: sutural biology, some well-known syndromes, and some unusual syndromes. , 2009, The Journal of craniofacial surgery.

[10]  J. Richtsmeier,et al.  Comparison of Craniofacial Phenotype in Craniosynostotic Rabbits Treated with Anti–Tgf-β2 at Suturectomy Site , 2008, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

[11]  Deepak M. Gupta,et al.  Cranial Sutures: A Brief Review , 2008, Plastic and reconstructive surgery.

[12]  D. Frim,et al.  Recurrence of Synostosis following Surgical Repair of Craniosynostosis , 2008, Plastic and reconstructive surgery.

[13]  A. Burrows,et al.  Noggin Inhibits Postoperative Resynostosis in Craniosynostotic Rabbits , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[14]  H. Losken,et al.  Anti-TGF-β2 Antibody Therapy Inhibits Postoperative Resynostosis in Craniosynostotic Rabbits , 2007, Plastic and reconstructive surgery.

[15]  H. Losken,et al.  Postoperative Anti-Tgf-&bgr;2 Antibody Therapy Improves Intracranial Volume and Craniofacial Growth in Craniosynostotic Rabbits , 2007, The Journal of craniofacial surgery.

[16]  P. Steinbok,et al.  Reformation of the sagittal suture following surgery for isolated sagittal craniosynostosis. , 2006, Journal of neurosurgery.

[17]  A. Moursi,et al.  Sustained delivery of bioactive cytokine using a dense collagen gel vehicle collagen gel delivery of bioactive cytokine. , 2006, Archives of oral biology.

[18]  Gillian M Morriss-Kay,et al.  Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies , 2005, Journal of anatomy.

[19]  M. Cohen.  Editorial: Perspectives on craniosynostosis , 2005, American journal of medical genetics. Part A.

[20]  R. Koepsel,et al.  Transforming Growth Factor-β Isoform Expression in the Perisutural Tissues of Craniosynostotic Rabbits , 2004 .

[21]  H. Losken,et al.  Rescue of coronal suture fusion using transforming growth factor-beta 3 (Tgf-beta 3) in rabbits with delayed-onset craniosynostosis. , 2003, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[22]  A. Moursi,et al.  Delivery of transforming growth factor-beta2-perturbing antibody in a collagen vehicle inhibits cranial suture fusion in calvarial organ culture. , 2003, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

[23]  J. Bonaventure,et al.  Molecular and cellular bases of syndromic craniosynostoses , 2003, Expert Reviews in Molecular Medicine.

[24]  D. Carlson,et al.  Tgf-beta1, Tgf-beta2, Tgf-beta3 and Msx2 expression is elevated during frontonasal suture morphogenesis and during active postnatal facial growth. , 2002, Orthodontics & craniofacial research.

[25]  A. Moursi,et al.  Transforming growth factor‐beta 3(Tgf‐β3) in a collagen gel delays fusion of the rat posterior interfrontal suture in vivo , 2002, The Anatomical record.

[26]  Galanis,et al.  Transforming growth factor‐β3 (Tgf‐β3) down‐regulates Tgf‐β receptor type I (Tβr‐I) during rescue of cranial sutures from osseous obliteration , 2002 .

[27]  L. Opperman,et al.  Transforming growth factor-beta3 (Tgf-beta3) down-regulates Tgf-beta3 receptor type I (Tbetar-I) during rescue of cranial sutures from osseous obliteration. , 2002, Orthodontics & craniofacial research.

[28]  M. Longaker,et al.  The pathogenesis of craniosynostosis in the fetus. , 2001, Yonsei medical journal.

[29]  P. Gakunga,et al.  Transforming growth factor‐β2 and TGF‐β3 regulate fetal rat cranial suture morphogenesis by regulating rates of cell proliferation and apoptosis , 2000 .

[30]  P. Gakunga,et al.  Transforming growth factor-beta 2 and TGF-beta 3 regulate fetal rat cranial suture morphogenesis by regulating rates of cell proliferation and apoptosis. , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[31]  R. W. Cho,et al.  Cranial suture obliteration is induced by removal of transforming growth factor (TGF)-beta 3 activity and prevented by removal of TGF-beta 2 activity from fetal rat calvaria in vitro. , 1999, Journal of Craniofacial Genetics and Developmental Biology.

[32]  C. Greene.  Pancraniosynostosis after surgery for single sutural craniosynostosis. , 1998, Pediatric neurosurgery.

[33]  J. McCarthy,et al.  Immunolocalization of transforming growth factor beta 1, beta 2, and beta 3 and insulin-like growth factor I in premature cranial suture fusion. , 1997, Plastic and reconstructive surgery.

[34]  H. Losken,et al.  Coronal Suture Pathology and Synostotic Progression in Rabbits with Congenital Craniosynostosis , 1996 .

[35]  H. Losken,et al.  Development of a strain of rabbits with congenital simple nonsyndromic coronal suture synostosis. Part II: Somatic and craniofacial growth patterns. , 1994, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

[36]  J. Persing,et al.  Calvartal Deformity Regeneration Following Subtotal Craniectomy for Craniosynostosis: A Case Report and Theoretical Implications , 1993 .

[37]  J. Persing,et al.  Calvarial deformity regeneration following subtotal craniectomy for craniosynostosis: a case report and theoretical implications. , 1993, The Journal of craniofacial surgery.

[38]  S. Pruzansky,et al.  Craniosynostosis : diagnosis, evaluation, and management , 1986 .

[39]  M. Cohen.  Craniosynostosis and syndromes with craniosynostosis: incidence, genetics, penetrance, variability, and new syndrome updating. , 1979, Birth defects original article series.

[40]  E. Alexander,et al.  Recurrent and multiple suture closures after craniectomy for craniosynostosis. , 1974, Journal of neurosurgery.