Move over Mickey, Minnie and even Mighty Mouse, because while cartoonists have created mice able to withstand falling anvils, researchers at the University have engineered mice with a bone structure that even the world’s most famous mice might be envious of.

Beth Dykstra
X-rays of femur mice bones with different Wnt10b levels. The left bone has increased Wnt10b protein levels causing a firmer bone development. The middle has normal levels, and the right has a decrease of Wnt10b, resulting in fractures. (courtesy of Ormon

Molecular and Integrative Physiology Prof. Ormond MacDougald and his fellow researchers have recently been experimenting with mice that have been genetically altered to produce less adipocytes, or fat cells, and produce four times more osteoblasts, or bone cells. Using these “super mice,” researchers are on their way to better understanding one possible mechanism for the development of osteoporosis in older adults, which may also help lead to a drug to treat the disease.

To produce the mice used in the study, an artificial sequence of DNA was injected into fertilized mouse eggs, causing these genetically altered mice to produce more of a certain signaling protein, called Wnt10b (pronounced Wint ten b) inside their bone marrow. Signaling proteins regulate the development of tissues in the body.

With higher levels of Wnt10b, the mice developed stronger and larger bones than usual. There is a patent pending on the genetically altered mice.

“There are many pharmaceutical companies that are very actively developing very small molecules or other approaches to activate this pathway with the hope of providing a drug that could be used to increase bone formation,” MacDougald said.

“Most of the drugs that are out there just inhibit the reabsorption of bone, and this would be a valuable tool within the tool kit that doctors have in treating osteoporosis,” he added.

Wnt10b is part of a family of 19 other Wnt signaling proteins, which all help determine the type of cells that bone marrow stem cells will become. These stem cells can give rise to many different tissues such as bone, fat, cartilage and connective tissue.

The Wnt10b signaling pathway can either block the formation of undifferentiated cells to fat cells, or encourage the production of bone cells, MacDougald said.

The findings from this study at the University will help researchers better understand how osteoporosis develops. Osteoporosis is a disease characterized by a decrease in bone mass. Left untreated, it can lead to a very high susceptibility to bone fractures and breaks. The discovery that the Wnt10b signaling protein causes an increase in bone cell formation helps researchers to better understand one mechanism of bone formation and may possibly help lead to drugs capable of regenerating lost bone mass.

The National Osteoporosis Foundation estimates that 55 percent of Americans over the age of 50 have osteoporosis, the vast majority of these being women who can lose 20 percent of their bone mass within a decade after menopause. As the baby boomer generation continues to age, these figures will likely increase, pushing the demand for medications to help prevent and cure the disease

However, Rackham student Christina Bennett, researcher and first author of the Wnt10b mice article, which was published Feb. 21, hopes a drug might be created as a result of the study, but does not necessarily think the findings will lead directly to a cure-all drug.

“Wnt’s are also involved in cancer so one of the concerns would be if you stimulate Wnt signaling you could also cause bone cancer,” Bennett said, though noting that cancer was not observed in any of the mice involved in the study. She added that in the development of a drug, a different protein or other molecule aside from Wnt10b that has the same effect but would be safer could be used instead.

Previous research conducted by MacDougald and other researchers last year showed that an excess of Wnt10b in fat cells of mice, instead of within the bone marrow, causes the mice to have 50 percent less body fat. This previous research on super skinny mice, also could help researchers better understand and treat obesity.

Bennett is quick to point out that a decrease in the fat cells as a side effect of a Wnt10b derived drug to increase bone mass in osteoporosis patients wouldn’t necessarily be detrimental.

“But isn’t that the perfect drug? I think a decrease of fat in bone marrow or elsewhere wouldn’t be a negative thing,” she said.

To quantitatively analyze the size and density of the bones within the studied mice, the research team utilized micro-computerized tomography, a type of three-dimensional X-ray machine. MacDougald said the results showed that the bones were stronger and larger and the mice were more resistant to bone loss that occurs along with estrogen depletion, which is similar to post-menopausal bone loss in women.

The researchers would not say exactly where they plan to go from here, but they do want to continue to study Wnt signaling and gain a better understanding of precisely how Wnts, especially Wnt10b, function.

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