In Greek myth, one glance at Medusa's snake-coifed head could turn a man to stone. But the villain in a rare inherited disease that relentlessly converts the body's soft connective tissues into bone-transforming its sufferers into living statues-has proved to be much more elusive. Indeed, it lurks within the victims' own immune systems, scientists in Philadelphia have discovered.
Bony prison. FOP fused the spine, shoulders, ribs, and elbows of this man, who died of pneumonia at age 39.
In children with the disease, called fibrodysplasia ossificans progressiva (FOP), the slightest injury to ligaments, tendons, or muscles can cause severe inflammation, followed by the appearance of cartilage, and then ordinary bone, at the site of the injury. As the disease progresses, sufferers' spines, limbs, rib cages, and jawbones fuse in place, leading to complete immobilization.
In the 22 August New England Joumal of Medicine, a team led by orthopedic surgeon Frederick Kaplan of the University of Pennsylvania School of Medicine now reports that this abnormal bone buildup occurs because the lymphocytes, or white blood cells, of people with FOP erroneously manufacture bone morphogenic protein-4 (BMP-4), a powerful signaling protein known to help build the skeleton of the developing embryo. "You should be able to repair and remodel bone later in life, but you shouldn't be able to make a new bone," Kaplan says. "That's what's happening here."
While developmental biologists have been studying BMPs and related proteins in organisms from fruit flies to humans since the 1960s, this is the first time a member of the BMP family has been implicated in a human genetic disease. "It's an amazing story," says developmental geneticist William Gelbart of Harvard University, who discovered the first BMP family member, the protein Decapentaplegic (DPP), which helps establish body and limb axes in the developing fruit fly, among other functions. "It's incredibly gratifying to see how central these molecules are in a whole host of developmental processes- and now in a human disease with heartbreaking effects." The discovery could eventually lead to a therapy to block either the production of BMP-4 or its effects.
The idea that a gene defect might underlie FOP originated about 7 years ago, Kaplan says, after he and geneticist Michael Zasloff, also at the University of Pennsylvania, found a small family in which both a parent and children were affected, indicating that the disorder is hereditary. In 1990, after learning that DPP's relatives, the newly discovered human proteins BMP-2 and BMP-4, help build limbs in the mammalian embryo by triggering bone-cell formation, Kaplan and Zasloff proposed that FOP might be caused by a genetic mutation affecting the production of one of the BMPs.
A test of the hypothesis had to wait until 1993, when Kaplan and Zasloff first obtained blood and tissue samples from patients with FOP. Penn medical student Adam Shafritz, now a resident physician at Manhattan's Hospital for Special Surgery, examined the samples, looking for messenger RNAs that would indicate that the BMP genes were active. He found one-corresponding to the BMP-4 gene-in the lymphocytes of 26 of 32 FOP patients studied, but in only one of 12 normal subjects.
That finding posed a puzzle, however, because if the lymphocytes were releasing BMP-4 into the bloodstream, it would be so diluted and short lived that it couldn't account for new bone growth in discrete locations around the body. Then, Kaplan recalls, the team found "the Rosetta stone for this whole condition": a biopsy sample taken 25 years earlier from a 4-year-old boy with FOP.
Under the microscope, the researchers saw masses of lymphocytes surrounding and choking off muscle cells. While a normal response to injury, in FOP patients, the researchers realized, this clumping must create high local concentrations of BMP-4, triggering bone growth. The lymphocytes of people with FOP, Kaplan and Zasloff conclude, probably carry a genetic error that improperly switches on production of BMP-4.
The researchers have now set out to locate this error, which may be in the regulatory regions of the BMP-4 gene itself or in some other gene whose product controls BMP-4 production. Already, however, the findings have heightened hopes for an eventual cure for FOP. "With so much being discovered about how the BMPs act," says Brigid Hogan, a developmental geneticist at Vanderbilt University in Nashville, Tennessee, "it might be possible to develop drugs that would block some part of the BMP-4 pathway - and therefore prevent the progression of what is a horrible, nightmare disease."
SCIENCE VOL. 273. 30 AUGUST 1996 pg. 1170
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