A Novel Low-Molecular-Weight Compound Enhances Ectopic Bone Formation and Fracture Repair

• Published in: Journal of bone and joint surgery. American volume 2013-03, Vol.95 (5), p.454-461
• Main Authors: Wong, Eugene, Sangadala, Sreedhara, Boden, Scott D, Yoshioka, Katsuhito, Hutton, William C, Oliver, Colleen, Titus, Louisa
• Format: Article
• Language: English
• Subjects: Animals; Biomechanical Phenomena; Bone Morphogenetic Protein 2 - pharmacology; Bone Morphogenetic Protein 2 - therapeutic use; Bony Callus - diagnostic imaging; Bony Callus - drug effects; Bony Callus - growth & development; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Femoral Fractures - diagnostic imaging; Femoral Fractures - drug therapy; Femoral Fractures - physiopathology; Fracture Healing - drug effects; Fractures, Closed - diagnostic imaging; Fractures, Closed - drug therapy; Fractures, Closed - physiopathology; Injections, Intralesional; Male; Models, Animal; Radiography; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Scientific; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta - therapeutic use; Treatment Outcome; Triazines - pharmacology; Triazines - therapeutic use; Ubiquitin-Protein Ligases - antagonists & inhibitors; Vinyl Compounds - pharmacology; Vinyl Compounds - therapeutic use
• ISSN: 0021-9355; 1535-1386
• DOI: 10.2106/JBJS.L.00275

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.