FIbrous dysplasia is a rare bone disorder, most often diagnosed ingirls under eight years of age, and in boys before nine and one-half.Their bones have the immature, embryonic structure in whichcollagen fibers are interlaced in an irregular meshwork called,descriptively, "woven bone," instead of the robust lamellar bonyplates of the adult skeleton.
In children with the disorder, bone does not mineralize properly, andhas poor mechanical properties, which lead to deformities andfractures.
McCune-Albright (McC-A) syndrome, which occurs early in fetaldevelopment, is a triad of symptoms. Besides fibrous dysplasia,other symptoms include precocious puberty in girls, and prematurecafe-au-lait "age spots" on youthful skin.
In fact, pediatricians often don't diagnose McC-A or fibrousdysplasia _ which may have begun developing before birth _ untilthe pain of an occult broken bone shows up the condition by X-ray orbiopsy.
Both McC-A and the separate dysplasia often progress to a not-so-rare cancer of childhood and early adulthood, osteogenic sarcoma.The surest treatment for this fast-growing malignancy of lower limbbones is amputation. Often, by the time the tumor has beendiagnosed, it's metastasized fatally to the lungs.
About one in 200 patients with fibrous dysplasia, and eight in 200McC-A cases, go on to develop osteosarcoma.
For treating McC-A and fibrous dysplasia, says molecular biologistRene St.-Arnaud of Shriner's Hospital in Montreal, "an experimentalprotocol at our hospital is using bis-phosphonates to try to regulatethe rapid turnover of bone associated with the lesions."
St.-Arnaud is senior author of a paper in the current New EnglandJournal of Medicine (NEJM) dated Thursday, and titled: "IncreasedExpression of the c-fos Proto-Oncogene in Bone From Patients WithFibrous Dysplasia."
"c-fos," St.-Arnaud told BioWorld Today, "was one of the very firstoncogenes isolated in the early 1980s. It was originally identified asthe transforming oncogene of osteosarcoma in mice." He added, "Inhumans, it's the normal gene that all of us have in our cells, notcausing cancer unless something happens to it."
High-Level c-fos Ubiquitous In Fibrous Bones
St.-Arnaud showed in his NEJM article that eight out of eight fibrousdysplasia patients had high levels of c-fos in their biopsied fibrousbone tissue. Their non-fibrous bones had none of the proto-oncogene,and samples from patients with other bone diseases had very lowlevels of c-fos .
"In the tissues that have the disease," he said, "there is increasedproduction of cyclic adenosine monophosphate (cAMP)" This, heexplained, "is secondary to a mutation in the stimulatory protein Gsa,coupled to adenylate cyclase, the enzyme that turns on cAMP. Thesystem is always in "ON" position, and produces cAMP all the time."
He continued, "But nobody knew, until our work, what happensdownstream of that event, which is an early occurrence at the cellsurface that triggers other events inside the cell. In bone we believethat the activation of c-fos expression is what occurs downstream ofthe cAMP event. And that would be responsible for the bone lesion."
Why bone in particular? "You can overexpress c-fos in a number oftissues, but bone is the only one affected," St.-Arnaud said. "If youhave too much or too little fos, that affects bone turnover anddevelopment." It's a known target of c-fos action."
In the McC-A syndrome, that Gsa protein is mutated and activated,he observed, "thus causing the cAMP overproduction." He pointedout that "in individuals with this mutation, perhaps fos is increased inother tissues than bone too, but without detrimental effect."
St.-Arnaud's group reported in NEJM that "Replacement of thearginine residue at position 201 of the Gsa subunit by either histidineor cysteine results in an abnormal Gsa protein that stimulatesadenylate cyclase."
In Situ Hybridization Pointed Up Proto-Oncogene Excess
To pin responsibility for too much c-fos onto the gene encoding theGsa protein, the Montreal co-authors employed in situ hybridizationto measure output of messenger RNA, which translates c-fos.
"Now," he said, "we are trying to develop a better way to diagnosethat Gsa mutation. At the moment, the procedure is extremely tricky,and there's a lot of variation from lab to lab, in trying to make aclear-cut molecular diagnosis of a patient." He went on, "Eventuallythe idea will be to make use of the information we have on c-fos, as amolecular tool to use when unsure of a diagnosis."
As an example he cited a much more malevolent disorder,osteogenesis imperfecta. (See BioWorld Today, May 23, 1995; p.1.)"In some cases, its lesion resembles fibrous dysplasia, so it is difficultto make the correct differential diagnosis. In such cases, we canprobe for fos expression." n
-- David N. Leff Science Editor
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