Scientists Describe How Chemical Turns Progenitor Stem Cells into Bone Cells

06 Sep 2004

A group of researchers from The Skaggs Institute for Chemical Biology at The
Scripps Research Institute and from the Genomics Institute of the Novartis
Research Foundation (GNF) have described how a small synthetic molecule called
"purmorphamine" causes a type of stem cell to selectively differentiate into adult
bone cells. Purmorphamine, or a similar compound that has the same effect, may
have significant clinical value someday for treating the bone-weakening disease
osteoporosis.

In the latest issue of the journal Chemistry & Biology, the researchers describe how
purmorphamine works by activating a signaling pathway inside the progenitor cells
known as "hedgehog signaling." Hedgehog signaling is involved in the development
of a number of cell types other than bone cells, including cells in the central nervous
system that are lost in the course of neurodegenerative diseases such as
Parkinson's.

"We knew that purmorphamine could differentiate cells into [bone cells]," says
researcher Xu Wu, who is a doctoral candidate in the Kellogg School of Science
and Technology at Scripps Research. "The discovery that it works through
hedgehog opens up the possibility that small molecules like purmorphamine might
be useful in the development of new medicines for the treatment of peripheral nerve
damage and Parkinson'sdisease."

Wu is the lead author of the study, to be published in an upcoming issue of the
journal Chemistry & Biology. The research was conducted under the direction of
Peter G. Schultz, who is a professor of chemistry and Scripps Family Chair of the
Skaggs Institute of Chemical Biology at The Scripps Research Institute, and Sheng
Ding, who is an assistant professor in the Scripps Research Department of
Chemistry.

Bone Growth, Bone Loss, and Osteoporosis

Dead bones are deceptively dry.

Those hard, fossilized skeletal objects on display in natural history museums have
survived long after the death and decomposition of all the other bodily tissues of the
animals that grew them because they are mineral-rich. These minerals help give
bones the strength they need to form the architectural support of the body.

But in living creatures, bones are made up of more than mere minerals. Living
bones are wet. They contain an abundance of live cells, blood vessels, water, and
other materials, and they are hotbeds of biological activity—bone marrow, for
instance, is where the body's red blood cells are produced.

One of the most important biological activities that takes place in bones throughout
life is the process of mineral deposition, which is the basis of bone growth and loss.
Early in life, bones grow from proliferating cartilage cells, which form columns within
the bone, pushing the older cells to the middle of the bone shaft. The matrix
between these cells is filled in with calcium deposits, and as the cartilage cells
mature, they enlarge and later die. Then the spaces they occupied become filled
with bone cells, called osteocytes, and blood vessels.

Osteocytes are responsible for managing the storage of calcium salts and other
minerals throughout life. Even after the more than 200 distinct bones in the human
body are completely "ossified" and stop growing in early adulthood, mineral
deposition and absorption still occurs in these bones because they are the
warehouses that store most of the body's calcium, phosphorous, and other essential
minerals.

Bone cells are constantly being replaced as we age, and throughout life, osteocytes
are created by bone cell precursors known as osteoblasts, which differentiate into
osteocytes.

Osteoblast differentiation is slower in older people, and beyond middle age the
process of mineral absorption begins to outpace the process of mineral deposition.
As a result, bone mass and mineral density decreases, bones become more porous,
and this can lead to bone weakening and the clinical condition known as
osteoporosis.

Osteoporosis, which literally means porous bone, currently afflicts some 10 million
Americans, according to the National Institutes of Health, and an additional 34
million more Americans have low bone mass, placing them at increased risk for this
condition. Estimated national direct expenditures (hospitals and nursing homes) for
osteoporosis and related fractures are $14 billion each year.

People with osteoporosis, because their bones are weakened, are more prone to
bone fractures, and osteoporosis causes more than 1.5 million fractures annually.
Often these are debilitating hip and wrist fractures that result from simple falls. The
spines of people with osteoporosis are also prone to breaking, and in dramatic
cases, the spine can collapse as a result of a simple sneeze.

Regenerative Medicine and Stem Cell Therapy

Stem cells and other multipotent progenitor cells have huge potential in medicine
because they have the ability to differentiate into many different cell
types—potentially replenishing cells that have been permanently lost by a patient.

The possibilities for this type of therapy are virtually unlimited. For instance,
neurodegenerative diseases like Parkinson's, in which dopaminergic neurons in the
brain are lost, might be ameliorated by giving a patient compounds that might
regenerate or protect neurons. Type I diabetes—in which beta cells in the pancreas
are permanently lost—might be treated by generating new beta cells. And
osteoporosis could potentially be treated with new bone cells derived from
progenitor cells.

But there are still formidable technological hurdles that must be surpassed before
these types of treatments are possible. One of the greatest of these hurdles is
understanding how to selectively differentiate stem cells into the particular cells of
interest. It's hard to control which specific lineage the stem cells differentiate into,
and one of scientists' great challenges is to find ways to selectively differentiate
stem cells into specific cell types.

In humans and other mammals, cells develop along a pathway of increasing
specialization in response to growth factors and other signals that initiate
developmental mechanisms inside the cell that scientists are only beginning to
understand. Cell differentiation occurs in response to growth factor proteins and
other "signal" molecules that bind to the outer portion of molecular receptors that
stretch across the membrane of the stem cells. The inside portion of these receptors
then initiate other events inside the cell that lead to the transformation of the cell.

One of 100,000 Small Molecules

A few years ago, Wu, Schultz, and Ding began looking for synthetic chemicals that
might cause stem cells to selectively differentiate into other types of cells. They
started to do high-throughput screening using technology developed at GNF.

High-throughput screening is a way of testing a large number of compounds for
those that have one particular ability. They were looking for chemicals that could
turn a type of mouse stem cell called a "multipotent mesenchymal progenitor cell,"
which has the ability to differentiate into bone, cartilage, and other types of cells,
into a mature bone cell.

The scientists screened some 100,000 small molecules from a combinatorial small
molecule library that they synthesized, and they found a small molecule called
purmorphamine that fit the bill.

Now Wu, Ding, Schultz, and their colleagues are reporting how purmorphamine
causes the multipotent mesenchymal progenitor cells to differentiate into mature
bone cells.

The scientists used high-density oligonucleotide microarrays, or "gene chips," to
monitor the gene expression pattern of stem cells following treatment with
purmorphamine, and this allowed them to identify a cluster of genes that were
upregulated when the cells were treated with the chemical.

They found that purmorphamine causes the mesenchymal progenitor cells to
differentiate into osteocytes by upregulating the signaling of a type of protein called
hedgehog, which activates a number of genes that promote proliferation and
differentiation, leading the cell to transform into an osteocyte.

Hedgehog signaling is also known to be involved in the differentiation of stem cells
to other cell types. For instance, one type of hedgehog signaling is involved in
neuronal proliferation, and this suggests that purmorphamine, as a compound that
activates hedgehog signaling, might have some protective effects against diseases
like Parkinson's or conditions like peripheral nerve damage. Another type of
hedgehog signaling leads to the differentiation of multipotent mesenchymal
progenitor cell into cartilage tissues. This suggests that purmorphamine might also
find application in diseases, like arthritis, where the repair of cartilage cells in the
knees or other tissues might have a beneficial effect.

"There are many possible avenues of research to pursue with purmorphamine,"
says Ding.

The article, "Purmorphamine Induces Osteogenesis by Activation of the Hedgehog
Signaling Pathway," is authored by Xu Wu, John Walker, Jie Zhang, Sheng Ding,
and Peter G. Schultz and appears in the August 23, 2004 issue of Chemistry &
Biology. See: http://www.chembiol.com

This work was supported by The Skaggs Institute for Research and the Novartis
Research Foundation.

By Jason Socrates Bardi,   [log in to unmask]

The Scripps Research Institute

For more information on diabetes click here.

Huge database of hospitals world wide .

SOURCE: Medical News Today, UK
http://www.medicalnewstoday.com/medicalnews.php?newsid=12975

* * *

----------------------------------------------------------------------
To sign-off Parkinsn send a message to: mailto:[log in to unmask]
In the body of the message put: signoff parkinsn