title: A novel low-molecular-weight compound enhances ectopic bone formation and fracture repair.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors: Department of Orthopaedics, Alfred Health, Prahram, VIC 3181, Australia. eugenelwwong@yahoo.com
authors: Eugene
authors: E
authors: Wong
authors: Sreedhara
authors: S
authors: Sangadala
authors: Scott D
authors: SD
authors: Boden
authors: Katsuhito
authors: K
authors: Yoshioka
authors: William C
authors: WC
authors: Hutton
authors: Colleen
authors: C
authors: Oliver
authors: Louisa
authors: L
authors: Titus
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology / Q000627:therapeutic use*; D002146:Bony Callus / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D017102:Fracture Healing / Q000187:drug effects*; D005596:Fractures, Closed / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D015552:Injections, Intralesional; D008297:Male; D023421:Models, Animal; D011859:Radiography; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors; D014753:Vinyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C500826:2-vinyl-4,6-diamino-1,3,5-triazine; D055396:Bone Morphogenetic Protein 2; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014227:Triazines; D014753:Vinyl Compounds; C499469:recombinant human bone morphogenetic protein-2; D044767:Ubiquitin-Protein Ligases