The Journal of Bone and Joint Surgery (American) 83:1789-1797 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
Effect of Anti-Tumor Necrosis Factor- Gene Therapy on Wear Debris-Induced Osteolysis
Lisa M. Childs, MS,
J. Jeffrey Goater, MS,
Regis J. O'Keefe, MD, PhD and
Edward M. Schwarz, PhD
Investigation performed at the University of Rochester Medical
Center, Rochester, New York
Lisa M. Childs, MS
Department of Microbiology and Immunology, University of Rochester
Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642.
E-mail address: lisachilds{at}mail.com
J. Jeffrey Goater, MS
Regis J. O’Keefe, MD, PhD
Edward M. Schwarz, PhD
Department of Orthopaedics, University of Rochester Medical Center,
601 Elmwood Avenue, Box 665, Rochester, NY 14642. E-mail address
for J.J. Goater: jeff_goater@urmc.rochester.edu.
E-mail address for R.J. O’Keefe: regis_okeefe@urmc.rochester.edu.
E-mail address for E.M. Schwarz: edward_schwarz@urmc.rochester.edu
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 (Public Health Service Grants
AR45971 and AR46545), the National Institute of Arthritis and Musculoskeletal and
Skin Diseases, and the Orthopaedic Research and Education 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.
Background: Particle phagocytosis by macrophages
induces the secretion of tumor necrosis factor- ,
which is involved in the development of an osteolytic response. Therefore,
we aimed to determine whether gene delivery of a soluble inhibitor
of tumor necrosis factor- (sTNFR:Fc) could prevent
wear debris-induced osteolysis in a mouse model. sTNFR:Fc
is a fusion protein containing the extracellular domain of the human
type-I tumor necrosis factor receptor fused to the Fc region of mouse
immunoglobulin. It acts by binding to tumor necrosis factor-
and preventing signaling through the membrane-bound tumor
necrosis factor receptors.
Methods: An adenoviral vector encoding the LacZ
gene (Ad.CMV-NlacZ) was propagated and was tested for its ability
to transduce calvarial tissue. Ad.CMV-TNFR:Fc (encoding
sTNFR:Fc) or Ad.CMV-NlacZ was administered to CBAxB6 mice
in the presence or absence of titanium particles implanted onto
the calvaria. Serum levels of sTNFR:Fc were measured with enzyme-linked
immunosorbent assay, and the mice were killed on the tenth postoperative
day for histological analysis. The experiments were repeated in
athymic nude mice to avoid complications associated with the adenovirus-specific immune
response.
Results: Administration of the control virus (Ad.CMV-NlacZ) transduced
10% of the cells in the periosteum. Ad.CMV-NlacZ
treatment of sham-treated or titanium-treated animals induced
significant bone resorption and osteoclastogenesis above control
levels (that is, those in animals not treated with a virus). Treatment with
the sTNFR:Fc virus did not reduce bone resorption or osteoclast
numbers below control levels in CBAxB6 mice. In the athymic mice,
no increase in the midline sagittal suture area or osteoclastogenesis
was observed after treatment with the control vector and sTNFR:Fc gene
therapy reduced the suture area to background levels.
Conclusions: An immunologic response to Ad.CMV-NlacZ
was most likely responsible for the increase in bone resorption and
osteoclastogenesis in the animals treated with the control vector
alone. In the athymic mice, in the absence of this immune response,
sTNFR:Fc gene therapy reduced bone resorption in the midline sagittal
suture area but had no effect on osteoclastogenesis.
Clinical Relevance: These results indicate that
adenoviral vectors should not be used for gene therapy for the prevention
of osteolysis. The results of adenovirus-mediated gene
therapy in other systems should also be questioned because of the strong
immune response to this vector. However, administration of the sTNFR:Fc
gene in a different, nonimmunogenic vector may be useful for the
treatment or prevention of wear debris-induced osteolysis.
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