A Novel Low-Molecular-Weight Compound Enhances Ectopic Bone
Formation and Fracture Repair
Eugene Wong, MD1;
Sreedhara Sangadala, PhD2; Scott D. Boden, MD3; Katsuhito
Yoshioka, MD4; William C. Hutton, DSc3; Colleen Oliver,
DVM2; Louisa Titus, PhD2
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.
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.
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.
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).
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.