Fall/Winter 2006 - University of Rochester Medical Center

appropriate levels in young mice that are
not expressed at those levels in old mice.
One of the genes that is down-regulated,
O’Keefe’s team discovered, involves the
same Smurf that is a culprit in the development
of arthritis. The lab also has
shown that COX-2, one of the cyclooxygenase
enzymes, may play an important
role in maintaining appropriate Smurf
levels and appears to be critical for fracture
healing.
“Smurf helps cause the transformation
of cartilage that forms in fracture
sites into bone,” Rosier said. “In the
joint, that’s a terrible thing, but in fractures,
it is part of a normal and necessary
process.”
The O’Keefe lab also identified an
intercellular signaling pathway that
controls the Smurf. The project will
investigate the cellular mechanisms in
maintaining the appropriate levels of
Smurf expression and the role of COX-2.
A parallel project directed by Puzas
and Susan Bukata, M.D., an orthopaedic
surgeon, involves a clinical trial of teraparatide,
a parathyroid hormone with
the brand name Forteo. The hormone
stimulates osteoblasts to form bone.
When used in treating severe cases of
osteoporosis, the hormone can increase
bone mass by 15 percent in a year.
“One of our notions is that the
hormone could substitute for the loss of
COX-2 that occurs with aging and restore
the signaling that would enable the
appropriate levels of the gene to be
expressed, so cartilage turns into bone on
schedule,” Rosier said.
Rosier’s team also is the first to
make a dramatic discovery about the
hormone’s capabilities when given to
patients with pelvic-insufficiency fractures.
These stress fractures often fail to
heal because they occur in elderly people
with other health problems. After discussions
with patients with the stress
fractures, several received the parathyroid
hormone.
“Some had been in pain and in a
wheelchair for a year,” Rosier said.
“ Within a few months of taking the
hormone, they walked into the clinic.
X-rays showed the fractures had healed.
We have now treated about 20 people,
with almost all having healed. We have,
in fact, had some patients with spine
fractures in the neck who have
completely healed.”
Puzas and his group will quantify
and map the healing of fractures in
patients in a clinical trial of the
hormone.
The third major part of the CORT
project addresses the revitalization of
allografts, the dead bone from human
cadavers used to replace bone lost in
severe trauma or cancer. Edward
Schwarz, Ph.D., associate professor of
orthopaedics, is the principal investigator.
“The transplanted bone works well
mechanically. It will fuse and provide
structural support, but it never becomes
a fully living bone,” Rosier said. “Fatigue
fractures occur, and there’s no ability to
repair. Living bone constantly repairs
itself. There is a high failure rate in the
long term for these allografts. It would be
great if we could find a way to convert
the graft to a living bone.”
Schwarz has conducted in-depth
studies of allografts in mice, tracking the
cells that produce healing and identifying
the growth factors involved. He
also has developed a novel gene therapy
that, when used in mice, causes a revascularization
of the bone and turns the
dead bone into living bone. Schwarz
will continue his gene therapy in mice
to demonstrate the extent and strength
of the revitalization.
Cone beam computed tomography
technology, developed by Ruola Ning,
Ph.D., professor of radiology at the
Medical Center, will be used to quantify
vascularity in human patients who
receive allografts. The CORT pilot study
will validate use of the technology to
quantify bone formation. It also could
lead to a clinical trial of a gene therapy
that would stimulate revitalization.
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