Mighty mouse helps researchers tackle osteoporosis

A genetically engineered 'mighty mouse' is helping Medical College of Georgia researchers find the best way for young people to build bone and avoid osteoporosis.

"We are interested in kids; we want to know how to maximize their bone during peak periods of growth while they still can," says Dr. Mark Hamrick, bone biologist. "One of the best predictors of who is going to get osteoporosis and who is not is how much bone you have at sexual maturity. So we want to know what people can do from zero to age 18 that really is going to pack that bone on." These mighty mice, with up to 70 percent more muscle mass than a regular mouse and essentially no body fat, and a $1 million grant from the National Institutes of Health are helping Dr. Hamrick answer that question. The mice lack the myostatin gene, a negative regulator of muscle mass. "Lots of genes control muscle development," says Dr. Hamrick. "This one is pretty significant in terms of not letting muscles get too big."

Myostatin is expressed at highest levels during development, when the embryo is growing, to ensure that muscles don't overgrow, Dr. Hamrick says. The level expressed changes naturally over the course of life. "It's still expressed as children grow and is present in very low levels in adults," he says. "It's suggested that you might get rises in myostatin levels with aging, which is associated with a loss of muscle mass that typically accompanies increased age. " Some muscle-wasting diseases as well as space flight and extended bed rest also are associated with increased myostatin levels. Numerous products claim to help adults build muscle by turning off this powerful muscle regulator produced by muscle cells, Dr. Hamrick says. But the only product scientifically proven to block myostatin is a monoclonal antibody now under study for its potential to treat muscular dystrophy, he says.

The muscular rodents that result when myostatin is taken out of the equation are enabling scientists to explore the hypothesis that one of the best ways to build bone is to build muscle.

"People have argued for many years that the way to increase bone density and strength is force – bones respond to the stress and strain placed on them by forming more bone – and the best way to increase that force is big muscles," says Dr. Hamrick. "We want to know if that is the case. We want to know if certain genes involved in bone formation are up-regulated with increased muscle and if these genes are stress-responsive genes.

"We also want to know if muscle can affect bone in other ways. Maybe it affects different hormones. Maybe it's a source of different growth factors itself. There's the frequency of a stimulus, not just the magnitude of it. There are also changes in blood and fluid flow that occur. We need to know the real mechanism."

And does it matter if the force put on bone comes from fat rather than muscle? "Some studies suggest that fat is a great predictor of bone mass and that it has protective effects on the bone in postmenopausal women," Dr. Hamrick says. Yet the growing number of obese children in the United States tend to have lower bone mass relative to their body weight than they should, he says.

"We can look at whether muscle has more of an impact on bone mass than fat because our mighty mice don't gain fat. So we can take two mice that weigh exactly the same, one mostly muscle and the other mostly fat, and compare bone mass," he says, using a rodent-sized bone density machine. "The other thing we want to know is, if you increase muscle mass through exercise, do you get the same amount of bone increase as you do by losing myostatin?"

That means taking normal mice, exercising them and looking at their bone mass relative to their muscle mass. He also is exercising the mighty mice, no small task because, unlike normal mice that happily run on a treadmill as long as you let them, these muscle-bound counterparts prefer to skip the workout. Interestingly, early evidence indicates that when myostatin knockout mice do exercise, it doesn't benefit their bones as much as the normal mice.

"Does an exercised normal mouse have the same amount of bone mass and strength as a regular mighty mouse that is just sitting around not exercising?" Dr. Hamrick asks, adding that early data indicates the answer may be yes. "I think what we are finding goes right along with what people at the MCG Georgia Prevention Institute are finding with studies of human exercise: there is no easy way out. The best way to make our kids strong, healthy and happy is a good diet and regular exercise. That is going to help their hearts, brains and bones. We see it in people. We are seeing it in mice."

Like many age-related infirmities, osteoporosis is becoming a bigger concern as people live longer, he says. Weak, fracture-prone bones likely are in the future for many children who today appear polar opposites: those too fat from overeating and inactivity or too frail from not eating because of an obsession with thinness, says the scientist and father.