coaxing bones to grow anew

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fresh~horses - 22 Oct 2005 17:20 GMT

"Using a protein that can seduce adult stem cells into becoming bone
tissue, Cameron Clokie, head of oral and maxillofacial surgery at the
University of Toronto, has pioneered a technique to reset the jaw's
skeletal clock - coaxing bones to grow as they do in a newborn baby.

"This is pretty much back to the embryonic state of bone
generation," Dr. Clokie said. "With this patient we've actually
regrown a jawbone that is identical [to the one] he lost."

snip

"...Mr. Russel underwent a four-hour operation that left him with
little more than a faint scar, and he spent just two nights in the
hospital: "Two weeks later, I was skiing in Colorado," he said. The
only lingering effect Mr. Russel described is numbness in his lower lip
and chin due because a sensory nerve had to be cut to remove the
tumour. "It's been amazing."

To reconstruct Mr. Russel's jaw, Dr. Clokie added a particular growth
protein to a putty-like gel that actually liquefies in the freezer and
solidifies in warmer temperatures. He then modelled it into the shape
of Mr. Russel's missing jaw piece. "You can imagine what it's like
trying to model a [jaw] shape from bone . . . it's like wood," Dr.
Clokie said. "This is like Play-Doh."

http://www.theglobeandmail.com/servlet/story/RTGAM.20051022.wxchin1022/BNStory/s
pecialScienceandHealth/

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Mark & Steven Bornfeld - 22 Oct 2005 18:36 GMT

> "Using a protein that can seduce adult stem cells into becoming bone
> tissue, Cameron Clokie, head of oral and maxillofacial surgery at the
[quoted text clipped - 22 lines]
>
> http://www.theglobeandmail.com/servlet/story/RTGAM.20051022.wxchin1022/BNStory/s
pecialScienceandHealth/

    I must say--I wonder what might really be going on here. I
particularly wonder about the use of the term "adult stem cells" in this
context.
    Most of the mandible is formed intramembranously, and is continuously
remodeled in life by the action of osteoblasts and osteoclasts. There
are no "stem cells" in healthy adult bone, though perhaps some primitive
blood-forming elements.
    In any case, while I can understand a claim to perhaps encourage
osteoblastic activity, implying here that there is some kind of
de-differentiation process going on is a dangerous concept.
    Bone reconstruction is a pretty old concept--grafting materials,
whether natural or not are intended as a matrix for the invasion of
osteogenic cells. Surgeons have a variety of materials that may be used.
    I would be interested in seeing a citation for the original research.

Steve

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Mark & Steven Bornfeld DDS
http://www.dentaltwins.com
Brooklyn, NY
718-258-5001

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Sean - 26 Oct 2005 21:19 GMT

> > "Using a protein that can seduce adult stem cells into becoming bone tissue,

Cameron Clokie, ....has pioneered a technique - coaxing bones to grow
as they do in a newborn baby.
http://www.theglobeandmail.com/servlet/story/RTGAM.20051022.wxchin1022/BNStory/s
pecialScienceandHealth/"

> I must say--I wonder what might really be going on here. I
> particularly wonder about the use of the term "adult stem cells" in this
[quoted text clipped - 10 lines]
> osteogenic cells. Surgeons have a variety of materials that may be used.
> I would be interested in seeing a citation for the original research.

Mark & Steve:

I have worked with Dr. Clokie, and was at the ChaRM conference
referenced in the Globe & Mail article.
There appears to be some misunderstanding based on the article and I
thought I'd do my best to respond to some of your comments:

You state "there are no "stem cells" in healthy adult bone"

However, it is well recognized that a multipotent cell which has
potential to differentiate into many different connective tissue cell
types (osteoblast, chondrocyte, myoblast, adipocyte) resides in all
connetive tissues. This cells is often desecribed as a mesenchymal stem
cell and is generally considered an "adult stem cell". It has not been
shown to be totipotent (able to make all tissues of the body), while in
theory an "embryonic stem cell" is.

This was demonstrated by the orthopaedic surgeon Marshall Urist in 1965
when he implanted pieces of bone matrix (from which the calcium was
removed) into muscle pouches and demonstrated that something from the
bone matrix stimulated cells within the muscle to differentiate into
osteoblasts and chondrocytes and make bone and cartilage [1]. Over the
proceeding 25 years the factor present in the bone matrix was
demonstrated to be a family of proteins called Bone Morphogenetic
Proteins (BMPs), and that DBM or BMPs could stimulate bone growth when
implanted in numerous non-osseous connective tissues.

You asked the question "I wonder what might really be going on here."

The way these BMP containing implants work is to stimulate these
multipotent mesenchymal cells to proliferate and differentiate into
osteoblasts and NOT to stimualte the osteoblasts present to make more
bone. These cells are present within the marrow spaces, within the
periosteum and also reside with the surrounding connective tissues.
There is also some evidence that they come in with the new blood
vessels.

The use of recombinant human BMP-7 (OP-1) and later rhBMP-2 (Infuse)
was approved by the FDA for use in various orthopaedic applications
over the last 5 years. The native protein extracted from bones has also
been used clinically although it is not available commercially [2].

You also commented that "implying here that there is some kind of
de-differentiation process going on is a dangerous concept"
There is NO de-differentiation process occurring. Rather these "adult
stem cells" are being stimulated (usually the term used is "induced")
to proliferate and differentiate into osteoblasts (there is no
de-differentiation of osteoblasts or other cells to a more "primative"
state and then re-differentiation)

As you pointed out bone grafting has been going on for a long time.
The point of the article was that this technique permits the surgeons
to remove bone and replace it with material OTHER than autologous bone
grafts taken from the leg, hip, or rib. Thus, there is only a single
surgery, less OR time, less recovery time and ultimately less cost, to
the patient or the health care system.

"I would be interested in seeing a citation for the original research"
I believe that Cameron has submitted (or will do so soon) a clinical
article on the use of recombinant BMP in oral surgery. He has publised
some work on using the purified protein (see reference 2 below). There
are many articles on its use clinically for non-union fractures and
spinal fusions (see reference 3 for an overview).

References:
[1] Urist, MR (1965). Bone: Formation by autoinduction. Science, 150 ,
893-899

[2] Moghadam HG, Urist MR, Sandor GK, Clokie CM. Successful mandibular
reconstruction using a BMP bioimplant. J Craniofac Surg. 2001
Mar;12(2):119-27; discussion 128

[3] Boden SD. The ABCs of BMPs. Orthop Nurs. 2005 Jan-Feb;24(1):49-52;
quiz 53-4.

If you don't have access to these artciles you can access freely a
summary of the clinical trials results and FDA approvals for the
various BMP preparations from:

http://www.cigna.com/health/provider/medical/procedural/coverage_positions/medic
al/mm_0118_coveragepositioncriteria_recombinant_human_bone_morphogenetic_protein
.pdf

Hope that clears up the confusion. If I missed anything post here and
I'll do my best to answer.

Sean.

Sean AF Peel (Ph.D.)
Sr. Scientist
Osteopharm Inc
Oakville, ON
CANADA

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