Bone morphogenetic proteins-signaling plays a role in tendon-to-bone healing: a study of rhBMP-2 and noggin.

摘要

BACKGROUND: Successful anterior cruciate ligament reconstruction requires secure healing between tendon and bone. HYPOTHESIS: Bone morphogenetic protein-signaling plays an important role in tendon-to-bone healing. rhBMP-2, a powerful osteoinductive agent, can improve tendon-bone interdigitation. STUDY DESIGN: 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. CONCLUSION: 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. CLINICAL RELEVANCE: 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.