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Raj Gopalakrishnan
Diagnostic and Biological Sciences
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When people
think of the University's School of Dentistry, they naturally first
think of teeth. For faculty, staff, and visitors alike, it's hard
not to; even the high-rise Moos Tower building that houses the school
is shaped like a "molar in the sky." For Raj Gopalakrishnan,
B.D.S., Ph.D., an assistant professor in the Department of Diagnostic
and Biological Sciences, his research is hardly all about teeth.
The basic research he performs on bone biology does have implications
for dental implants, periodontal health, oral pathology, oral surgery,
endodontics, and orthodontics. But talk to him for a few minutes,
and it becomes clear that his work pertains to the whole human body.
Building and losing bone
Gopalakrishnan, a board-certified oral pathologist, is primarily
interested in mechanisms of bone formation; in particular, how molecules
involved in the pathways that increase or decrease bone density
are regulated and therefore may affect bone development. One major
project currently underway in his laboratory is a study of parathyroid
hormone (PTH) and its regulation of mineralization, or
hardening, of bone that occurs as it matures. "In the body,
PTH is required to maintain calcium balance," says Gopalakrishnan.
"If blood calcium levels decrease, the body signals to the
parathyroid gland, which secretes PTH. The PTH travels to cells
in bone and signals them to start to resorb bone. Calcium is released
from [the resorbing] bone and returns blood calcium levels to normal."
Gopalakrishnan studies osteoblasts, the cells in the body
that make bone, by growing them in culture dishes. In initial studies,
when he added PTH to cultured osteoblasts, he found that the osteoblasts
did not undergo mineralization. Through additional studies, he demonstrated
that a particular inhibitor protein, called matrix Gla protein
(MGP), was induced by PTH in cell culture and prevented mineralization
from occurring in cultured osteoblasts. "These studies are
important because they help us to understand PTH's basic function
and physiology. But they are also relevant to hyperparathyroidism,
which is caused by hyperplasia or tumors of the parathyroid gland
or by other conditions, such as renal failure, that can cause a
chronic depression of blood calcium levels. This depression leads
to compensatory overactivity of the parathyroid gland. One of the
major complications of hyperparathyroidism is osteoporosis,"
notes Gopalakrishnan.
One intriguing aspect of this work, according to Gopalakrishnan,
relates to the treatment of osteoporosis, which is an abnormal
loss of bone density and weight that can cause pain, loss of physical
height, and fractures. Although PTH has been shown in osteoblast
cultures to inhibit mineralization and therefore bone formation,
when PTH was given to humans and animals in a specific regimen,
it actually increased bone formation. The Food and Drug Administration
has recently approved the use of PTH for the treatment of osteoporosis.
Gopalakrishnan's continued studies of PTH's effects on MGP and the
mineralization process may shed light on the molecular mechanisms
of how PTH can cause both bone loss and bone formation.
The relevance of this basic bone biology research goes beyond the
pathogenesis and treatment of osteoporosis. Gopalakrishnan notes
that another protein, called PTH-related protein, which works through
the same receptor on osteoblasts as PTH, has been found by scientists
to be important in metastasis of cancer to the bone (which is frequently
observed in both breast and prostate cancer). Gopalakrishnan plans
to eventually expand his scope to include studies of bone cancer
and bone metastasis. In addition, the use of PTH to regenerate bone
is of potential interest to dentists, because preliminary results
by others suggest that it could be used to build bone at sites where
periodontal disease has caused bone loss.
Developing bone and other organs
Another significant focus in Gopalakrishnan's laboratory is a study
in collaboration with Anna Petryk, a pediatric endocrinologist in
the Medical School, on bone morphogenetic protein (BMP).
Despite its name, BMP is important not just in the development of
bone, but also of a number of other tissues (for example, the brain,
eye, craniofacial structures, heart, and lung). BMP is involved
in a variety of cellular processes, including cell proliferation,
cell differentiation, and programmed cell death. More specifically,
Gopalakrishnan and Petryk are studying a BMP-binding protein called
twisted gastrulation (Tsg). In studies of osteoblasts in
cell culture, they found that adding Tsg inhibits both the development
of premature osteoblasts into mature osteoblasts and osteoblast
mineralization. They attributed this effect to Tsg binding BMP and
thus blocking the BMP signaling required for normal development.
Given this result, Gopalakrishnan and Petryk predicted that mice
deficient in Tsg would produce more bone, since Tsg was not present
to inhibit BMP and its stimulation of bone growth. Instead, they
found the Tsg-deficient mice actually had decreased bone density.
In addition, Petryk's laboratory found that these Tsg-deficient
mice had craniofacial defects, including the loss of the lower jaw.
To better understand the mechanisms of Tsg's effect on bone formation
and BMP function, Gopalakrishnan and Petryk intend to investigate
the interactions between BMP, Tsg, and other BMP-binding proteins.
Gopalakrishnan speaks enthusiastically of his collaboration with
Petryk, which arose by serendipity. Shortly after his arrival at
the U of M three years ago, Gopalakrishnan gave a seminar, which
Petryk attended. A few weeks later, they were riding in the same
elevator and, having heard his talk and knowing that he was an oral
pathologist, Petryk commented to him that jaw development appeared
abnormal in her Tsg-deficient mice. Gopalakrishnan visited her laboratory
and examined the mice, and from there a successful working relationship
began. Gopalakrishnan and Petryk will continue their work together,
thanks in part to their shared Academic Health Center faculty development
grant, "Twisted gastrulation and bone formation."
Raj Gopalakrishnan's faculty profile: www1.umn.edu/dental/faculty_pages/gopalakrishnanr.html
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