The Journal of Bone and Joint Surgery (American) 85:2332-2342 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.
In Vivo Somatic Cell Gene Transfer of an Engineered Noggin Mutein Prevents BMP4-Induced Heterotopic Ossification
David L. Glaser, MD1,
Aris N. Economides, PhD3,
Lili Wang, PhD2,
Xia Liu, MS3,
Robert D. Kimble, PhD3,
James P. Fandl, PhD3,
James M. Wilson, MD, PhD2,
Neil Stahl, PhD3,
Frederick S. Kaplan, MD1 and
Eileen M. Shore, PhD1
1 Department of Orthopaedic Surgery, University of Pennsylvania, 424 Stemmler
Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6081. E-mail address for
D.L. Glaser:
david.glaser{at}uphs.upenn.edu.
E-mail address for F. S. Kaplan:
frederick.kaplan{at}uphs.upenn.edu
2 Medical Genetics Division, Department of Medicine, University of Pennsylvania,
424 Stemmler Hall, 36th and Hamilton Walk, Philadelphia, PA 19104-6081. E-mail
address for D.L. Glaser:
david.glaser{at}uphs.upenn.edu.
E-mail address for F. S. Kaplan:
frederick.kaplan{at}uphs.upenn.edu
3 Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591.
E-mail address for A.N. Economides:
aris{at}regpha.com
Investigation performed at Regeneron Pharmaceuticals, Tarrytown, New
York, and the Departments of Orthopaedic Surgery and Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania
In support of their research or preparation of this manuscript, one or more
of the authors received grants or outside funding from the International
Fibrodysplasia Ossificans Progressiva Association, the Center for Research in
FOP and Related Disorders, the Ian Cali Fund, the Isaac and Rose Nassau
Professorship of Orthopaedic Molecular Medicine, and the National Institutes
of Health (R01-AR41916). They did not receive 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.
Background: The formation of the skeleton requires inductive signals
that are balanced with their antagonists in a highly regulated negative
feedback system. Inappropriate or excessive expression of BMPs (bone
morphogenetic proteins) or their antagonists results in genetic disorders
affecting the skeleton, such as fibrodysplasia ossificans progressiva. BMP
signaling mediated through binding to its receptors is a critical step in the
induction of abnormal ossification. Therefore, we hypothesized that
engineering more effective inhibitors of this BMP-signaling process may lead
to the development of therapies for such conditions.
Methods: BMP4-induced heterotopic ossification was used as a model
for testing the ability of the BMP antagonist Noggin to block de novo bone
formation, either by local or systemic delivery. Since Noggin naturally acts
locally, a Noggin mutein, hNOG B2, was engineered and was shown to
circulate systemically, and its ability to block heterotopic ossification was
tested in a mouse model with use of adenovirus-mediated somatic cell gene
transfer.
Results: A mouse model of BMP4-induced heterotopic ossification was
developed. Local delivery of wild-type NOG inhibited heterotopic ossification,
but systemic administration was ineffective. In contrast, systemic delivery of
the adenovirus encoding hNOGB2 resulted in systemic levels that
persisted for more than two weeks and were sufficient to block BMP4-induced
heterotopic ossification.
Conclusions: BMP4-induced heterotopic ossification can be prevented
in vivo either by local delivery of wild-type Noggin or after somatic cell
gene transfer of a Noggin mutein, hNOGB2. Furthermore, the data in the
present study provide proof of concept that a naturally occurring factor can
be engineered for systemic delivery toward a desirable pharmacological
outcome.
Clinical Relevance: Blocking bone formation is clinically relevant
to disorders of heterotopic ossification in humans, such as fibrodysplasia
ossificans progressiva. Furthermore, development of BMP antagonists as
therapeutic agents may provide modalities for the treatment of other
pathologic conditions that arise from aberrant expression of BMPs and/or from
a lack of their antagonists.
 CiteULike  Connotea  Del.icio.us  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
G. K. Deirmengian, N. M. Hebela, M. O'Connell, D. L. Glaser, E. M. Shore, and F. S. Kaplan
Proximal Tibial Osteochondromas in Patients with Fibrodysplasia Ossificans Progressiva
J. Bone Joint Surg. Am.,
February 1, 2008;
90(2):
366 - 374.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. S. KAPLAN, J. GROPPE, R. J. PIGNOLO, and E. M. SHORE
Morphogen Receptor Genes and Metamorphogenes: Skeleton Keys to Metamorphosis
Ann. N.Y. Acad. Sci.,
November 1, 2007;
1116(1):
113 - 133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. S. Kaplan, D. L. Glaser, E. M. Shore, R. J. Pignolo, M. Xu, Y. Zhang, D. Senitzer, S. J. Forman, and S. G. Emerson
Hematopoietic Stem-Cell Contribution to Ectopic Skeletogenesis
J. Bone Joint Surg. Am.,
February 1, 2007;
89(2):
347 - 357.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Jiao, P. C. Billings, M. P. O'Connell, F. S. Kaplan, E. M. Shore, and D. L. Glaser
Heparan Sulfate Proteoglycans (HSPGs) Modulate BMP2 Osteogenic Bioactivity in C2C12 Cells
J. Biol. Chem.,
January 12, 2007;
282(2):
1080 - 1086.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
F. S. KAPLAN, J. FIORI, L. S. DE LA PENA, J. AHN, P. C. BILLINGS, and E. M. SHORE
Dysregulation of the BMP-4 Signaling Pathway in Fibrodysplasia Ossificans Progressiva
Ann. N.Y. Acad. Sci.,
April 1, 2006;
1068(1):
54 - 65.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. A. Kitterman, S. Kantanie, D. M. Rocke, and F. S. Kaplan
Iatrogenic Harm Caused by Diagnostic Errors in Fibrodysplasia Ossificans Progressiva
Pediatrics,
November 1, 2005;
116(5):
e654 - e661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.F. Termaat, F.C. Den Boer, F.C. Bakker, P. Patka, and H.J.Th.M. Haarman
Bone Morphogenetic Proteins. Development and Clinical Efficacy in the Treatment of Fractures and Bone Defects
J. Bone Joint Surg. Am.,
June 1, 2005;
87(6):
1367 - 1378.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.D.M. Collett and A.E. Canfield
Angiogenesis and Pericytes in the Initiation of Ectopic Calcification
Circ. Res.,
May 13, 2005;
96(9):
930 - 938.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Kan, M. Hu, W. A. Gomes, and J. A. Kessler
Transgenic Mice Overexpressing BMP4 Develop a Fibrodysplasia Ossificans Progressiva (FOP)-Like Phenotype
Am. J. Pathol.,
October 1, 2004;
165(4):
1107 - 1115.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. S. Kaplan, D. L. Glaser, N. Hebela, and E. M. Shore
Heterotopic Ossification
J. Am. Acad. Ortho. Surg.,
March 1, 2004;
12(2):
116 - 125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
