This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Letters to the Editor: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Letters to the Editor are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hannallah, D.
Right arrow Articles by Huard, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hannallah, D.
Right arrow Articles by Huard, J.
Related Collections
Right arrow Basic Science
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Facebook   Add to Technorati   Add to Twitter  
What's this?
The Journal of Bone and Joint Surgery (American) 86:80-91 (2004)
© 2004 The Journal of Bone and Joint Surgery, Inc.

Retroviral Delivery of Noggin Inhibits the Formation of Heterotopic Ossification Induced by BMP-4, Demineralized Bone Matrix, and Trauma in an Animal Model

David Hannallah, MD, MSc1, Hairong Peng, MD, PhD1, Brett Young, BSc1, Arvydas Usas, MD1, Brian Gearhart, BSc1 and Johnny Huard, PhD1

1 Department of Orthopaedic Surgery (D.H., H.P., A.U., and J.H.) and Departments of Molecular Genetics and Biochemistry and BioEngineering (J.H.), University of Pittsburgh; Growth and Development Laboratory (D.H., H.P., B.Y, A.U., B.G., and J.H.), Children's Hospital of Pittsburgh, 4100 Rangos Research Center, 3705 Fifth Avenue, Pittsburgh, PA 15213-2582. E-mail address for J. Huard: jhuard{at}pitt.edu

Investigation performed at the Department of Orthopaedic Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, and the Growth and Development Laboratory, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the National Institutes of Health (R01-DE 13420-01A2-JH) as well as the William F. and Jean W. Donaldson endowed chair at the Children's Hospital of Pittsburgh, the Henry J. Mankin endowed chair at the University of Pittsburgh, and the Hirtzel Foundation. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

This paper was the winner of the American Orthopaedic Association-Zimmer Travel Award for Orthopaedic Residents, 2002.

Background: The heterotopic ossification of muscles, tendons, and ligaments is a common problem faced by orthopaedic surgeons. We investigated the ability of Noggin (a BMP [bone morphogenetic protein] antagonist) to inhibit heterotopic ossification.

Methods: Part 1: A retroviral vector carrying the gene encoding human Noggin was developed and used to transduce muscle-derived stem cells. Part 2: Cells transduced with BMP-4 were implanted into both hind limbs of mice along with either an equal number, twice the number, or three times the number of Noggin-expressing muscle-derived stem cells (treated limb) or with nontransduced muscle-derived stem cells (control limb). At four weeks, the mice were killed and radiographs were made to look for evidence of heterotopic ossification. Part 3: Eighty milligrams of human demineralized bone matrix was implanted into the hind limbs of SCID (severe combined immunodeficiency strain) mice along with 100,000, 500,000, or 1,000,000 Noggin-expressing muscle-derived stem cells (treated limbs) or nontransduced muscle-derived stem cells (control limbs). At eight weeks, the mice were killed and radiographs were made. Part 4: Immunocompetent mice underwent bilateral Achilles tenotomy along with the implantation of 1,000,000 Noggin-expressing muscle-derived stem cells (treated limbs) or nontransduced muscle-derived stem cells (control limbs). At ten weeks, the mice were killed and radiographs were made.

Results: Part 1: An in vitro BMP inhibition assay demonstrated that Noggin was expressed by muscle-derived stem cells at a level of 280 ng per million cells per twenty-four hours. Part 2: Three varying doses of Noggin-expressing muscle-derived stem cells inhibited the heterotopic ossification elicited by BMP-4-expressing muscle-derived stem cells. Heterotopic ossification was reduced in a dose-dependent manner by 53%, 74%, and 99%, respectively (p < 0.05). Part 3: Each of three varying doses of Noggin-expressing muscle-derived stem cells significantly inhibited the heterotopic ossification elicited by demineralized bone matrix. Heterotopic ossification was reduced by 91%, 99%, and 99%, respectively (p < 0.05). Part 4: All eleven animals that underwent Achilles tenotomy developed heterotopic ossification at the site of the injury in the control limbs. In contrast, the limbs treated with the Noggin-expressing muscle-derived stem cells had a reduction in the formation of heterotopic ossification of 83% and eight of the eleven animals had no radiographic evidence of heterotopic ossification (p < 0.05).

Conclusions: The delivery of Noggin mediated by muscle-derived stem cells can inhibit heterotopic ossification caused by BMP-4, demineralized bone matrix, and trauma in an animal model.

Clinical Relevance: Gene therapy to deliver Noggin may become a powerful method to inhibit heterotopic ossification in targeted areas of the body.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Facebook Facebook   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 JBJSHome page
H. Hosalkar, J. Hsu, N. K. Pandya, and M. A. Keenan
What's New in Orthopaedic Rehabilitation
J. Bone Joint Surg. Am., October 1, 2008; 90(10): 2301 - 2311.
[Full Text] [PDF]

Home page
 J Am Acad Orthop SurgHome page
C. B. Gates, T. Karthikeyan, F. Fu, and J. Huard
Regenerative Medicine for the Musculoskeletal System Based on Muscle-derived Stem Cells
J. Am. Acad. Ortho. Surg., February 1, 2008; 16(2): 68 - 76.
[Abstract] [Full Text] [PDF]

Home page
 J Am Acad Orthop SurgHome page
B. K. Potter, T. C. Burns, A. P. Lacap, R. R. Granville, and D. Gajewski
Heterotopic Ossification in the Residual Limbs of Traumatic and Combat-Related Amputees
J. Am. Acad. Ortho. Surg., September 1, 2006; 14(10): S191 - S197.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
D. Vernet, G. Nolazco, L. Cantini, T. R. Magee, A. Qian, J. Rajfer, and N. F. Gonzalez-Cadavid
Evidence That Osteogenic Progenitor Cells in the Human Tunica Albuginea May Originate from Stem Cells: Implications for Peyronie Disease
Biol Reprod, December 1, 2005; 73(6): 1199 - 1210.
[Abstract] [Full Text] [PDF]

Home page
 Am J Sports MedHome page
T. A. H. Jarvinen, T. L. N. Jarvinen, M. Kaariainen, H. Kalimo, and M. Jarvinen
Muscle Injuries: Biology and Treatment
Am. J. Sports Med., May 1, 2005; 33(5): 745 - 764.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
N. Hebela, D. G. Smith, and M. A. Keenan
What's New in Orthopaedic Rehabilitation
J. Bone Joint Surg. Am., November 1, 2004; 86(11): 2577 - 2581.
[Full Text] [PDF]