March 13th, 2004
AOSSM Specialty Day

BMP-Signaling Plays a Role in Tendon-to-Bone Healing: A Study of rhBMP-2 and Noggin

Authors:
  1. C. Benjamin Ma MD, University of California, San Francisco, San Francisco, CA
  2. Sumito Kawamura MD, Hospital for Special Surgery, New York, NY
  3. XingHua Deng MD, Hospital for Special Surgery, New York, NY
  4. Lily Ying, Hospital for Special Surgery, New York, NY
  5. Scott A. Rodeo MD, Hospital for Special Surgery, New York, NY
Objective:  Since healing of a soft tissue graft in a bone tunnel requires osteointegration, it is likely that BMPs play an important role in regulation of healing. This study tests the hypothesis that rhBMP-2 stimulates and noggin (a BMP inhibitor) inhibits healing of a tendon graft in a bone tunnel.
Methods:  21 mature New Zealand rabbits underwent bilateral ACL reconstruction with an autologous tendon graft. Three rabbits each received rhBMP-2 (11.5, 50 or 115mg) or noggin (10, 15, 30 and 100ng), applied to the tendon-bone interface using a calcium phosphate carrier (alpha-BSM). Contralateral controls received only the calcium phosphate carrier. Animals were sacrificed at 2 weeks and the tissues were analyzed using high resolution radiographs and histomorphometric analysis of tendon diameter, width of new bone formation (NBF) and width of the tendon-bone interface (IF) using computerized image analysis.
Results:  rhBMP-2 treatment led to a significant increase in new bone formation around the graft in a dose-dependent fashion (0.24-0.35mm vs 0.13-0.16mm for control (Figure One). There was a positive dose-dependent effect of BMP-2, with increases of 50%, 120% and 118% in the width of NBF. rhBMP-2 treatment also decreased the width of the fibrous tendon-bone interface. All dosages of noggin inhibited NBF from 38-60% (0.06-0.1mm vs 0.15-0.16mm for control), with a concomitant 14-60% increase in the width of the fibrous tendon-bone interface (Figure Two). There was no dose-dependent effect in the noggin concentrations studied. High resolution radiographs demonstrated increased radiodensity and a decrease in tunnel diameter in the rhBMP-2 group, while the noggin group was not significantly different than control.
Figure 1
The width of new bone formation at 2 weeks following surgery. The agents studied were rhBMP-2 (11.5, 50 or 115mg) and noggin (10, 15, 30 and 100ng). The contralateral side received calcium phosphate carrier (alpha-BSM) only. There was a significant dose-dependent effect of rhBMP-2 while there was no dose-dependent effect with noggin.
Figure 2
Histological images of the tibial bone tunnel (original magnification x 32). A. 10ng Noggin group: Note the thick interface layer with no obvious new bone formation. B. 115mg rhBMP-2 group: Note the infiltrating new bone within the tendon graft and minimal interface layer. The black marker represents 100mm.
Conclusions:  rhBMP-2 demonstrated a strong, positive dose-dependent effect on osteointegration at the tendon-bone junction, while noggin, a potent BMP inhibitor, decreased osteoblastic activity. These findings indicate that BMPs play an important role in tendon healing to bone.
References:  
  1. Rodeo et al, Use of recombinant human bone morphogenetic protein-2 to enhance tendon healing in a bone tunnel. AJSM 1999; 27(4):476-88.
  2. Martinek et al, Enhancement of tendon-bone integration of anterior cruciate ligament grafts with BMP-2 gene transfer:a histological and biomechanical study. JBJS 2002;84A(7):1123-31
Acknowledgements:  
Keywords:
  1. Cell Biology
  2. Ligament
 Categories:
  1. BASIC SCIENCE: Knee - ACL