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Topic Name: Skeletal Discovery: Bone cells affect metabolism
Category: Genetic Engineering
Research persons: Gerard Karsenty
Location: 701 West 168th Street,Room 1602A ,New York, NY 10032, United States
Details
If your blood glucose is out of whack, the problem may be in your bones. New research in mice shows that bone cells exert a surprising influence on
how the body regulates sugar, energy, and fat. The discovery could lead to new ways to treat type 2 diabetes, a disease involving poor regulation
of blood glucose. It also means that skeletons act as endocrine organs, which affect other body tissues by releasing hormones into the bloodstream.
"I'm already changing my teaching slides" about the functions of bones, comments Jennifer Westendorf, an associate professor of orthopedic surgery at
the Mayo Clinic in Rochester, Minn. "Now we can add that [the skeleton] affects energy metabolism as well," she says. "It's certainly an exciting
breakthrough." The team announcing the finding, led by Gerard Karsenty of Columbia University, had previously found that fat cells secrete a
hormone that influences bone-forming cells called osteoblasts. Because hormone regulation between two cell types is often reciprocal, Karsenty and his
team reasoned that osteoblasts might also be emitting hormones that control fat tissue. Osteoblasts make bone throughout a healthy person's lifetime,
while cells called osteoclasts tear down bone—processes that constantly remodel the skeleton. Osteocalcin, a somewhat enigmatic protein produced
only by osteoblasts, seemed like a good hormone candidate, Karsenty says. "[It] has been the flagship molecule of the [bone-research] field for 30
years, but nobody knew what it was doing." Karsenty's team fed a normal diet to mice engineered to lack the gene for osteocalcin. The mice became
obese and had low blood concentrations of insulin, a key hormone for controlling blood glucose. The animals also had poor sensitivity to insulin, a
hallmark of people with diabetes. Another group of mice, which had been engineered to have extra osteocalcin, stayed thin despite being fed a
high-calorie diet. These animals also maintained higher insulin concentrations and better sensitivity to insulin than the mice lacking osteocalcin
did, the team reports in the Aug. 10 Cell. Further tests on mice showed that osteocalcin causes the insulin-making cells in the pancreas to
proliferate and ramp up insulin production. The bone protein also causes fat cells to store less fat and to secrete a hormone called adiponectin. In
people as well as in mice, this substance improves cells' sensitivity to insulin. Previous research has shown that many people with type 2 diabetes
have low blood concentrations of osteocalcin. "Osteocalcin, if everything goes well, could be a treatment for type 2 diabetes. That's where the
excitement is," Karsenty says. Columbia University holds a patent on the idea, and Karsenty says that he's helping form a company to commercialize the
treatment. "This could also have important ramifications for cardiovascular disease because of the effect on metabolic syndrome," a condition
related to diabetes, comments Dana T. Graves of Boston University. "The fact that bone cells regulate energy metabolism, and that they do it through
osteocalcin, is a major finding," he says. A
Molecular Genetic Analysis of Skeletal Biology by Gerard Karsenty
As it is the case for every organ two distinct questions face biologists studying
skeleton. Those are how does it develop, and how does it execute its functions? In the first 10 years of its existence our laboratory focused its
effort on the developmental aspect of skeletal biology and tried to elucidate the transcriptional network controlling bone formation. This
resulted in the identification of positive and negative regulations of osteoblast differentiation. In particular, the lab identified Runx2 as the
master gene of osteoblast differentiation and ATF4 as the main regulator of osteoblast functions.
Without abandoning totally this line of research the lab is now focusing mainly on
skeleton physiology. More precisely we are asking three related questions: what are all the functions of the skeleton? What is the genetic cascade
accounting for these functions? And lastly, can we use this knowledge to understand the molecular bases of various diseases and to propose adopted
therapies? The work in this area started on bone remodeling, the process whereby bone mass is maintained constant throughout adulthood. Because of
some clinical information we hypothesized that bone mass, body weight and reproduction must be regulated by the same hormones. Testing this
hypothesis in vivo led us to show that the adipocyte-derived hormone leptin does regulate appetite, reproduction and bone mass. We further showed
that this requires the involvement of hypothalamic neurons that affect bone mass through two neuron mediators, the sympathetic tone and CART
(cocaine amphetamine regulated transcript). This work provided more improved understanding of the pathophysiology of osteoporosis, the main
disease of bone remodeling, and suggested a rationale treatment for this disease. We are now looking at various unanswered molecular aspects of
this novel regulation of bone mass.
The regulation of bone mass by leptin an adipocyte-derived hormone begged the
following question, are osteoblasts exerting a feed-back regulation of adipocytes? In other words is bone and endocrine organ regulating energy
metabolism? While testing this hypothesis we have identified two genes regulating not only adipocyte biology but also pancreas biology we have
also shown that these tow genes are located in the same pathway. This novel line of research is rapidly expanding in the laboratory as it not only
verifies the concept of a common endocrine regulation of bone mass and body weight but it also provides additional clues to the pathogenesis of
the most frequent degenerative diseases in developed countries, the metabolic syndrome.
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