Featured Research

from universities, journals, and other organizations

Signaling Protein Builds Bigger, Better Bones In Mice

Date:
February 24, 2005
Source:
University Of Michigan Health Sciences System
Summary:
Leaping tall buildings in a single bound may be out of the question, but the genetically engineered "supermice" in Ormond MacDougald's laboratory at the University of Michigan Medical School are definitely stronger than average. With bone mass up to four times greater than ordinary mice, these research animals could hold the secret to new drugs for preventing or treating osteoporosis and other human diseases.

ANN ARBOR, Mich. – Leaping tall buildings in a single bound may be out of the question, but the genetically engineered "supermice" in Ormond MacDougald's laboratory at the University of Michigan Medical School are definitely stronger than average. With bone mass up to four times greater than ordinary mice, these research animals could hold the secret to new drugs for preventing or treating osteoporosis and other human diseases.

The secret appears to be a secreted signaling protein called Wnt10b. Known to inhibit the development of adipose tissue in mice, Wnt10b also stimulates the growth of bone cells, according to a new study that will be published February 21 in the Online Early Edition of the Proceedings of the National Academy of Sciences.

"High levels of Wnt10b expression in bone marrow directly increased bone mass and density in our experimental mice," says Ormond A. MacDougald, Ph.D., associate professor of molecular and integrative physiology in the U-M Medical School. "This is the first identification of a specific signaling protein in the Wnt family that regulates bone formation."

Wnt10b is one of a family of 19 related proteins. Wnts (pronounced "wints") regulate the complex changes that take place as an embryo develops. One step in this process determines the fate of primitive cells called mesenchymal stem cells.

"In bone marrow, mesenchymal stem cells have the potential to become either fat cells called adipocytes or bone-forming cells called osteoblasts," MacDougald says. "In adult animals, including humans, there's a reciprocal relationship between bone and marrow fat. Our research indicates that Wnt10b's signal blocks the fat cell pathway and stimulates the osteoblast pathway, which means less fat and more bone."

To study the effect of Wnt10b gene expression on tissue development, MacDougald's research team created an artificial sequence of DNA called a transgene linking Wnt10b to the FABP4 promoter, which is expressed in fatty tissue and in bone marrow. U-M scientists injected the transgene DNA into fertilized mouse eggs, and then bred mice that inherited the new gene to create the transgenic animals used in their research.

Kurt D. Hankenson, D.V.M., Ph.D., a U-M assistant professor of orthopedic surgery and laboratory animal medicine, and Christina N. Bennett, a U-M graduate student and first author of the PNAS paper, used a technology called micro-computerized tomography to scan femur (leg) bones from mice that inherited the FABP4-Wnt10b gene combination and compare them to scans from normal mice.

Bennett and Hankenson discovered that femurs from the transgenic mice had almost four times as much bone, and were mechanically stronger than femurs from control mice. (Note to editors: An image showing the femur scan comparison is available.)

"It was a very exciting moment the first time we saw scans showing increased bone mass in transgenic mice," Bennett says. "Visually, we don't see any abnormal side-effects in bone from the transgenic mice. Its development and morphology appear to be completely normal."

Loss of bone often develops with aging, but Wnt10b transgenic mice maintained their high levels of bone mass up to the ripe old age of 23 months, when the study was concluded.

Estrogen deficiency in females is another common cause of bone loss. When U-M scientists removed ovaries from normal mice in the study, they developed reduced bone mineral density and bone volume. But the Wnt10b females showed no bone loss after their ovaries were removed. "Because the transgenic mice have more trabecular bone, or bone within the marrow cavity, to begin with, they are doubly protected from the usual loss of bone density due to estrogen deficiency," MacDougald adds.

To confirm that Wnt10b was the key to increased bone formation, Bennett and Hankenson scanned bones from a strain of laboratory mice that didn't have a gene for Wnt10b. Lacking the ability to produce Wnt10b protein in bone marrow cells, these mice had 30 percent lower bone volume and bone mineral density than normal mice.

Using PCR analysis of Wnt10b-expressing cells in bone marrow, MacDougald found high levels of collagen and alkaline phosphatase, and expression of transcription factors that turn on genes involved in bone formation.

Bennett discovered another important clue when she found that Wnt10b expression shuts down activity of a gene called PPAR-gamma, which is required for the development of adipocytes or fat cells. "It suggests that Wnt10b's role may be to block PPAR-gamma, shifting development from the adipocyte pathway to the osteoblast pathway," she says.

In future research, MacDougald hopes to unravel the molecular mechanism for Wnt10b's bone-building effect. "It's not only an important scientific question, it's important to the understanding and potential treatment of osteoporosis and other human diseases," he says. "Right now, there is a need for drugs on the market to stimulate new bone formation. Being able to activate Wnt signaling in bone marrow and osteoblasts might help prevent the loss of bone associated with aging or menopause."

The research was funded by the National Institutes of Health, the U-M Diabetes Research and Training Center, the U-M Core Center for Musculoskeletal Disorders, and the Nathan Shock Mutant and Transgenic Rodent Core. Fellowships to Christina Bennett were from the Tissue Engineering and Regeneration Training Grant and the American Physiological Society Porter Fellowship. Kenneth Longo was supported by a mentor-based postdoctoral fellowship from the American Diabetes Association.

The experimental mice used in the study were produced in the U-M's Transgenic Animal Model Core facility. The University of Michigan has filed for patent protection on the Wnt10b transgenic mouse.

Additional collaborators on the study include Kenneth A. Longo, Ph.D., a former research fellow in MacDougald's lab who is now a postdoctoral fellow in the U-M School of Dentistry; Wendy S. Wright, research associate; Larry J. Suva, Ph.D., Center for Orthopaedic Research, University of Arkansas for Medical Sciences; and Timothy F. Lane, Ph.D., Jonsson Comprehensive Cancer Center, University of California, Los Angeles, who developed the Wnt10b knock-out mouse.

MacDougald and his research team published a paper in the August 2004 issue of the Journal of Biological Chemistry, which showed that Wnt10b over-expression in adipocytes produced mice with 50 percent less body fat and fewer fat cells.

###

Reference: Regulation of osteoblastogenesis and bone mass by Wnt10b, PNAS Early Online Edition, www.pnas.org_cgi_doi_10.1073_pnas.0408742102. To appear in print March 1, 2005, vol. 102, no. 9


Story Source:

The above story is based on materials provided by University Of Michigan Health Sciences System. Note: Materials may be edited for content and length.


Cite This Page:

University Of Michigan Health Sciences System. "Signaling Protein Builds Bigger, Better Bones In Mice." ScienceDaily. ScienceDaily, 24 February 2005. <www.sciencedaily.com/releases/2005/02/050223164325.htm>.
University Of Michigan Health Sciences System. (2005, February 24). Signaling Protein Builds Bigger, Better Bones In Mice. ScienceDaily. Retrieved April 20, 2014 from www.sciencedaily.com/releases/2005/02/050223164325.htm
University Of Michigan Health Sciences System. "Signaling Protein Builds Bigger, Better Bones In Mice." ScienceDaily. www.sciencedaily.com/releases/2005/02/050223164325.htm (accessed April 20, 2014).

Share This



More Health & Medicine News

Sunday, April 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Nine-Month-Old Baby Can't Open His Mouth

Nine-Month-Old Baby Can't Open His Mouth

Newsy (Apr. 19, 2014) Nine-month-old Wyatt Scott was born with a rare disorder called congenital trismus, which prevents him from opening his mouth. Video provided by Newsy
Powered by NewsLook.com
'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Little Progress Made In Fighting Food Poisoning, CDC Says

Little Progress Made In Fighting Food Poisoning, CDC Says

Newsy (Apr. 18, 2014) A new report shows rates of two foodborne infections increased in the U.S. in recent years, while salmonella actually dropped 9 percent. Video provided by Newsy
Powered by NewsLook.com
Scientists Create Stem Cells From Adult Skin Cells

Scientists Create Stem Cells From Adult Skin Cells

Newsy (Apr. 17, 2014) The breakthrough could mean a cure for some serious diseases and even the possibility of human cloning, but it's all still a way off. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins