title: Bone morphogenetic proteins-signaling plays a role in tendon-to-bone healing: a study of rhBMP-2 and noggin.
abstract: BACKGROUND
  Successful anterior cruciate ligament reconstruction requires secure healing between tendon and bone.
  
  
  OBJECTIVE
  Bone morphogenetic protein-signaling plays an important role in tendon-to-bone healing. rhBMP-2, a powerful osteoinductive agent, can improve tendon-bone interdigitation.
  
  
  METHODS
  Controlled laboratory study.
  
  
  METHODS
  The study was designed in 2 phases: Phase I consisted of a dose-response study where 21 New Zealand White rabbits underwent bilateral anterior cruciate ligament reconstructions. Rabbits received either rhBMP-2 (11.5, 50, or 115 microg) or noggin (10, 15, 30, or 100 ng) (a potent bone morphogenetic proteins inhibitor) delivered in an injectable calcium phosphate matrix. Animals were sacrificed at 2 weeks and histomorphometric analyses were performed. In phase II, 60 rabbits underwent bilateral anterior cruciate ligament reconstructions and were assigned to 3 groups: rhBMP-2 (115 microg), noggin (30 ng) in a calcium phosphate carrier, and calcium phosphate carrier alone. Animals were sacrificed at 2, 4, and 8 weeks and histomorphometric and biomechanical analyses were performed.
  
  
  RESULTS
  rhBMP-2 treatment led to a significant increase in the width of new bone formation at the tendon-bone interface in a dose-dependent fashion (0.24-0.35 mm vs 0.13-0.16 mm in controls). All dosages of noggin inhibited new bone formation (0.06-0.1 mm vs 0.15-0.16 mm in controls); however, there was no dose-dependent effect in the concentrations studied. In the phase II study, rhBMP-2 resulted in a significant increase in new bone formation (81%, 89%, and 113%) at increasing time periods compared with controls. Tunnel diameters in the rhBMP-2 group were significantly smaller (15%-45%) than in the carrier group. The negative effect of noggin was not sustained, as new bone formation increased with time. The rhBMP-2 group demonstrated significantly increased stiffness at 8 weeks, while there was no significant difference in ultimate tensile load when compared with the other 2 groups.
  
  
  CONCLUSIONS
  rhBMP-2 demonstrated a strong, positive dose-dependent effect on osteointegration at the tendon-bone junction. In contrast, noggin decreased osteointegration. No tunnel widening was detected with rhBMP-2 using the calcium phosphate carrier.
  
  
  CONCLUSIONS
  Further studies are needed to investigate the potential clinical application of enhancing healing and decreasing recovery time using bone morphogenetic proteins in soft tissue ligament reconstruction.
authors.affiliation: University of California, San Francisco, Department of Orthopaedic Surgery, 500 Parnassus Avenue, MU 320W, San Francisco, CA 94143. maben@orthosurg.ucsf.edu.
authors.forename: C Benjamin
authors.initials: CB
authors.lastname: Ma
authors.forename: Sumito
authors.initials: S
authors.lastname: Kawamura
authors.forename: Xiang-Hua
authors.initials: XH
authors.lastname: Deng
authors.forename: Ling
authors.initials: L
authors.lastname: Ying
authors.forename: Jason
authors.initials: J
authors.lastname: Schneidkraut
authors.forename: Peyton
authors.initials: P
authors.lastname: Hays
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rodeo
mesh_terms: D000818:Animals; D016118:Anterior Cruciate Ligament / Q000601:surgery*; D001696:Biomechanical Phenomena; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000502:physiology* / Q000627:therapeutic use; D001861:Bone Regeneration / Q000187:drug effects; D001862:Bone Resorption; D001842:Bone and Bones / Q000502:physiology*; D002130:Calcium Phosphates; D002352:Carrier Proteins; D008297:Male; D023421:Models, Animal; D016348:Osseointegration; D011817:Rabbits; D011994:Recombinant Proteins / Q000627:therapeutic use*; D019651:Plastic Surgery Procedures / Q000379:methods*; D012307:Risk Factors; D015398:Signal Transduction; D013710:Tendons / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000627:therapeutic use*; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002130:Calcium Phosphates; D002352:Carrier Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C499469:recombinant human bone morphogenetic protein-2; C020243:calcium phosphate