Noggin inhibits postoperative resynostosis in craniosynostotic rabbits.
Inhibition of bone formation after surgery to correct craniosynostosis would alleviate the need for secondary surgeries and decrease morbidity and mortality. This study used a single dose of Noggin protein to prevent resynostosis and improve postoperative outcomes in a rabbit model of craniosynostosis.


BACKGROUND
Craniosynostosis is defined as the premature fusion of one or more of the cranial sutures, which causes secondary deformations of the cranial vault, cranial base, and brain. Current surgical intervention involves extirpation of the fused suture to allow unrestricted brain growth. However, resynostosis of the extirpated regions often occurs. Several bone morphogenetic proteins (BMPs), well-described inducers of ossification, are involved in bone healing. This study tested the hypothesis that a postoperative treatment with Noggin, an extracellular BMP inhibitor, can inhibit resynostosis in a rabbit model of human familial nonsyndromic craniosynostosis.


METHODS
Thirty-one New Zealand white rabbits with bilateral coronal suture synostosis were divided into three groups: (1) suturectomy controls (n = 13); (2) suturectomy with BSA in a slow-resorbing collagen vehicle, (n = 8); and (3) suturectomy with Noggin in a slow-resorbing collagen vehicle (n = 10). At 10 days of age, a 3 x 15-mm coronal suturectomy was performed. The sites in groups 2 and 3 were immediately filled with BSA-loaded gel or Noggin-loaded gel, respectively. Serial 3D-CT scan reconstructions of the defects and standard radiographs were obtained at 10, 25, 42, and 84 days of age, and the sutures were harvested for histological analysis.


RESULTS
Radiographic analysis revealed that Noggin-treated animals had significantly greater coronal suture marker separation by 25 days and significantly greater craniofacial length at 84 days of age compared with controls. 3D-CT analysis revealed that Noggin treatment led to significantly greater defect areas through 84 days and to increased intracranial volumes at 84 days of age compared with other groups. Histological analysis supported CT data, showing that the untreated and BSA-treated groups had significant healing of the suturectomy site, whereas the Noggin-treated group had incomplete wound healing.


CONCLUSIONS
These data support our hypothesis that inhibition of BMP activity using Noggin may prevent postoperative resynostosis in this rabbit model. These findings also suggest that Noggin therapy may have potential clinical use to prevent postoperative resynostosis in infants with craniosynostosis.
Cooper
Gregory M
GM
Department of Surgery, Division of Pediatric Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. greg.cooper@chp.edu
Curry
Chris
C
Barbano
Timothy E
TE
Burrows
Anne M
AM
Vecchione
Lisa
L
Caccamese
John F
JF
Norbutt
Craig S
CS
Costello
Bernard J
BJ
Losee
Joseph E
JE
Moursi
Amr M
AM
Huard
Johnny
J
Mooney
Mark P
MP
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002352:Carrier Proteins / Q000494:pharmacology*; D002508:Cephalometry; D003398:Craniosynostoses / Q000139:chemically induced / Q000517:prevention & control*; D004195:Disease Models, Animal; D011184:Postoperative Period; D011817:Rabbits; D012008:Recurrence; D014057:Tomography, X-Ray Computed; D000099176:Noggin Protein
D002352:Carrier Proteins; D000099176:Noggin Protein