TY  - JOUR
T1  - A Novel Low-Molecular-Weight Compound Enhances Ectopic Bone Formation and Fracture Repair
AU  - Wong, Eugene
AU  - Sangadala, Sreedhara
AU  - Boden, Scott D.
AU  - Yoshioka, Katsuhito
AU  - Hutton, William C.
AU  - Oliver, Colleen
AU  - Titus, Louisa
Y1  - 2013/03/06
N1  - 10.2106/JBJS.L.00275
JO  - The Journal of Bone & Joint Surgery
SP  - 454
EP  - 461
VL  - 95
IS  - 5
N2  - Background: 
  Use of recombinant human bone morphogenetic protein-2 (rhBMP-2) is expensive and may cause local side effects. A small synthetic molecule, SVAK-12, has recently been shown in vitro to potentiate rhBMP-2-induced transdifferentiation of myoblasts into the osteoblastic phenotype. The aims of this study were to test the ability of SVAK-12 to enhance bone formation in a rodent ectopic model and to test whether a single percutaneous injection of SVAK-12 can accelerate callus formation in a rodent femoral fracture model.Methods: 
  Collagen disks with rhBMP-2 alone or with rhBMP-2 and SVAK-12 were implanted in a standard athymic rat chest ectopic model, and radiographic analysis was performed at four weeks. In a second set of rats (Sprague-Dawley), SVAK-12 was percutaneously injected into the site of a closed femoral fracture. The fractures were analyzed radiographically and biomechanically (with torsional testing) five weeks after surgery.Results: 
  In the ectopic model, there was dose-dependent enhancement of rhBMP-2 activity with use of SVAK-12 at doses of 100 to 500 μg. In the fracture model, the SVAK-12-treated group had significantly higher radiographic healing scores than the untreated group (p = 0.028). Biomechanical testing revealed that the fractured femora in the 200 to 250-μg SVAK-12 group were 43% stronger (p = 0.008) and 93% stiffer (p = 0.014) than those in the control group. In summary, at five weeks the femoral fracture group injected with SVAK-12 showed significantly improved radiographic and biomechanical evidence of healing compared with the controls.Conclusions: 
  A single local dose of a low-molecular-weight compound, SVAK-12, enhanced bone-healing in the presence of low-dose exogenous rhBMP-2 (in the ectopic model) and endogenous rhBMPs (in the femoral fracture model).Clinical Relevance: 
  This study demonstrates that rhBMP-2 responsiveness can be enhanced by a novel small molecule, SVAK-12. Local application of anabolic small molecules has the potential for potentiating and accelerating fracture-healing. Use of this small molecule to lower required doses of rhBMPs might both decrease their cost and improve their safety profile.
SN  - 0021-9355
M3  - doi: 10.2106/JBJS.L.00275
UR  - http://dx.doi.org/10.2106/JBJS.L.00275
ER  -