By David N. Leff

Law enforcement agencies are increasingly constructing physical and psychological "profiles" of criminals on their wanted lists.

Molecular biologist Marian Young, at the National Institutes of Health's National Institute of Dental Research (NIDR), in Bethesda, Md., is pursuing the trail of a perpetrator of broken bones and death with the following profile.

Sex: female; age: 50's to 60's (i.e., postmenopausal); body build: lean, with "dowager's hump"; complexion: fair; lifestyle: sedentary; race: Caucasian or Asian.

The name on this rap sheet is osteoporosis, which Young described as "a significant burden to Western societies. The disease strips the body's skeleton of bone mass, density and strength. Osteoporotic fractures are a major cause of disability and death, costing billions of health-care dollars annually."

Young is chief of the molecular biology research program on bones and teeth at NIDR. "The disease mainly starts after menopause," she observed. "This is the big problem. Depletion of the estrogen hormone causes severe loss in the balance of the bone mass in the body, between formation and resorption. This is the fundamental driving hypothesis that we have," she added, "on what regulates bone mass and density.

"After menopause, with the loss of estrogen, that balance is disrupted. There is not enough bone formation to accommodate the resorption, and you get less and less mass. If you look at the bone in cross-section, it resembles a sponge," she said.

The hallmark of osteoporosis is bone fracturing.

Young recalled one individual who reached for a salt shaker and broke a vertebra. "They're so fragile," she explained, "they crush easily. And once we move into the realm of hip fracture, that requires bed rest — and it's a downhill spiral to the end."

She cited a grim statistic: "One woman in three, and one man in six will have a hip fracture as the result of osteoporosis."

An abundant component in maintaining bone integrity is biglycan. "Maybe some individuals have naturally higher levels of this protein in their genetic makeup than others," Young surmised, "which might explain why we have so much variability in osteoporosis."

Previous studies of the biglycan gene, Bgn, have shown that its expression level in humans may be related to stature. Knockout mice, denied Bgn, have proved to be faithful mimics of human osteoporosis.

Young is senior author of a paper in the September issue of Nature Genetics titled "Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice."

New Angle On Bone Formation

"The unique finding of our experiments with these biglycan-minus animals," Young told BioWorld Today, "is that it caused a defect of bone formation rather than resorption."

"We bred the knockouts," she said, "and at first when we looked at them we thought, 'Okay, we know that they're being born, and making bones more or less the right structure. So, it's not an early developmental effect in utero, [but] more an aging defect.'

"As the biglycan knockout mice could not accumulate bone, the longer we let them live, the more difference in bone mass we could note; they were just not making it at the same level as their normal littermates," she said. "The other side of the question, bone resorption, we could determine by measuring the area of the osteoclast — that's the cell that breaks down bone. It was unchanged between the normal wild-type mouse and the mutant knockout.

"A mouse's normal lifespan," she observed, "is a couple of years. Sexual maturity occurs about three weeks after birth. That's when we can tell the difference between males and females. They start mating at about five weeks.

"In fact," she went on, "that's when we start to see the bone defects. They're very, very subtle at first, and are related to time. As in humans, they progress with aging."

Biglycan belongs to a large family of small proteoglycans, of which another member is the protein decorin. "It, too, is made by mineralized tissue," Young said. "What we want to do now is create a double knockout, lacking both the decorin and biglycan genes. We want to find out if decorin can compensate for the absence of biglycan."

The other thing Young and her co-authors are doing is "taking precursor stem cells from the bone marrow of the biglycan-minus mice, which we know are able to form bone. These murine stromal stem cells should help us try to dissect out in vitro some of the mechanisms of biglycan's actions."

But First Things First

Young is hoping that the knockout mice will be useful for screening purposes. "Since we know they have a defect in bone formation," she asked, "could one look at the pharmaceutical industry's battery of compounds for something that could intervene at that level? Something that could then be novel compared to the drugs we now have available?"

The two leading osteoporosis prescription drugs now on the market — for estrogen replacement and resorption inhibition, respectively — tackle the resorption side of the bone balance.

"So, I hope that I can drum up some interest," Young said, "where I can lease out the mouse colonies to the private sector, academia, government — whoever wants them. The way it works is we don't actually patent them here at NIDR, but we lease them in a negotiated arrangement.

"I want to see them used to try to intervene in this process that gets screwed up, and maybe find new methods or therapies to cure the disease," she concluded. *