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Clockwise from left: Matt Warman targets LRP5 to build bone, Brendan Lee linked Notch signaling to bone cancer, and David Kingsley placed BMPs in the center of early bone-building efforts.
The work is essential. By 2020, half of all Americans over age 50 will have weak bones and the low bone mass of osteoporosis, according to a 2004 Surgeon General’s Report. Roughly 4 in 10 white women age 50 or older in the United States will experience a hip, spine, or wrist fracture, most likely due to osteoporosis. And the problem isn’t limited to women. Up to one in four men over age 50 will break a bone due to the disease. The consequences are profound: one in four patients over 50 with a hip fracture will die within a year.
“Skeletal diseases are incredibly common,” says developmental biologist David Kingsley, an HHMI investigator at Stanford University School of Medicine, noting that patients with less common but devastating bone diseases desperately need effective treatments too.
The discovery meant, Kingsley says, “that there is some magic in bone that could induce formation of new bone.”
Studying bone also sheds light on fascinating and fundamental biological questions, Kingsley adds. The development of bone reveals how “just a few cell types can be organized into highly specific shapes and sizes that underlie the things that animals do.” The forms of animal skeletons, past and present, offer clues about how their owners flew, ran, swam, and ate. Bone can do all that—but only if it stays in balance.
The Magic in Bone
Early in embryonic development, our bones are mostly cartilage, and it’s the cartilage-filled ends of bones that lengthen as we grow. As we mature and growth slows, bone gradually replaces that cartilage. The thick, hard outer layer of bone resembles reinforced concrete in its structure, deriving strength from fibrous proteins called collagen encrusted with crystals of a calcium-containing mineral. Even hard bone is plumbed with blood vessels and wired with nerves. And inside the outer layer sits marrow, a softer tissue packed with immature cells that can form blood, bone, and cartilage cells.
In 1992, Kingsley reported a pivotal discovery about how the body constructs bones. He examined a mutant line of mice with very short ears, a wide skull, and a reduced ability to heal fractured ribs in search of something that had been hinted at two decades earlier. An orthopedic surgeon named Marshall Urist had made an extract of rabbit bone and implanted it under the skin of a living rabbit. It produced an intact, marrow-filled bone under the rabbit’s skin. The discovery meant, Kingsley says, “that there is some magic in bone that could induce formation of new bone.”
He found that the short-eared mice had a mutation in a gene that produced that magic ingredient, called bone morphogenetic protein (BMP). Today 20 related BMPs are known, many of which induce the body to make bone or cartilage. BMP-2 is the active ingredient of a drug that grows new bone after spinal fusion surgery. Surgeons implant a biodegradable sponge soaked with the drug, called INFUSE Bone Graft by Medtronic. The procedure replaces an older, painful, and infection-prone method in which surgeons transplanted bone from the patient’s hip.
The same drug is used for other dental and orthopedic problems: to bolster bone that anchors crowns or teeth, to heal foot and ankle injuries, and to repair gunshot wounds to the jaw. It can help knit shin bones shattered in motorcycle accidents, for example, or replace sections of cancerous bone that have been removed in children, according to bone cell biologist Hari Reddi, of University of California, Davis, who purified the first BMPs in the 1980s.
However, the drug must be implanted with the sponge, rather than given as a pill or injected into the bloodstream, because it doesn’t easily circulate to where it’s needed, according to Reddi.
Clinicians would like better alternatives, and they need treatments that preserve and repair bone when it gradually deteriorates throughout the body, as it does in osteoporosis.
Building Bone Bulk
Even when bone is healthy, it’s always growing, dying, changing. To build and maintain healthy bone, we need weight-bearing exercise such as tennis, hiking, and walking; a healthy diet with calcium-rich food such as milk, cheese, and certain vegetables; and vitamin D, from dairy products and sunlight, or a supplement. This is true during childhood and adolescence when the body builds 85 percent of adult bone mass, and it’s true during adulthood to prevent bones from thinning and weakening.
Photos: Warman: Matt Kalinowski, Lee: Pam Francis, Kingsley: David Tower Kingsley