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Scientific Articles   |    
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
1 Department of Orthopaedics, Alfred Health, P.O. Box 315, Prahram, VIC 3181, Australia. E-mail address: eugenelwwong@yahoo.com
2 VA Medical Center-Research Service, 1670 Clairmont Road, Decatur, GA 30033. E-mail address for S. Sangadala: ssangad@emory.edu. E-mail address for C. Oliver: Colleen.Oliver@va.gov. E-mail address for L. Titus: ftitus@emory.edu
3 Emory Orthopaedic and Spine Center, 59 Executive Park South, Suite 3000, Atlanta, GA 30320. E-mail address for S.D. Boden: sboden@emory.edu. E-mail address for W.C. Hutton: whutton@emory.edu
4 Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, 920-8641, Japan. E-mail address: Ortho1976ky@yahoo.co.jp
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Investigation performed at the Atlanta Veterans Affairs Medical Center and Emory University School of Medicine, Atlanta, Georgia



Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

Copyright © 2013 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2013 Mar 06;95(5):454-461. doi: 10.2106/JBJS.L.00275
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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).

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.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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