|
|
 |
| Endocrinologist Suzanne Jan de Beur, tracking the phosphate regulatory pathway |
In 1985, Jean Russell began experiencing bone and muscle pain so severe that she could hardly move. Doctors at the Northern Pennsylvania community hospital where she worked couldn’t make sense of her symptoms and attributed them to stress. For two years, Russell suffered. Then, in 1987, University of Pennsylvania doctors discovered small fractures throughout her body and diagnosed Russell with osteomalacia, a softening of bone. While vitamin D supplements kept the disease in check, Russell began having painful flare-ups. She consulted with Hopkins endocrinologist Suzanne Jan de Beur, M.D., who suspected that tiny tumors were the cause. Lab tests confirmed low phosphorous levels and oncogenic osteomalacia.
It’s cases like these, Jan de Beur says, that have prompted her to dive head first into research of this very rare but debilitating disease to improve detection and treatment. Too often oncogenic osteomalacia is missed, mistaken for arthritis, bone cancer or even emotional stress, and patients endure unbearable pain that could have been prevented.
“It’s pretty compelling how symptomatic these patients are and how long they go undiagnosed,” says Jan de Beur. “Yet, when we remove their tumors, the syndrome completely abates.”
Jan de Beur’s lab has been conducting an anthropological-like dig into the disease and why these tumors have such a profound effect on phosphate in the body. In patients, phosphate is lost in the urine because the kidneys fail to hold on to it. Something in the tumors is promoting phosphate loss, a factor known as phosphatonin.
The answer, Jan de Beur says, lies in the regulatory path of phosphate. But to get at it, she has taken a different tack. While researchers tend to target proteins by purifying and propagating the tumors, which can cause them to lose their activity, Jan de Beur is looking at how genes in the tumors are expressed. By comparing their expression profiles, her lab has been able to identify upregulated genes in the tumors that are key players in bone mineralization, matrix formation, mineral ion homeostasis – the building blocks of bones. Interestingly, Ja de Beur says, two highly expressed genes, PHEX and FGF-23, are mutated in congenital forms of hypophosphatemia, diseases marked by low levels of phosphate and osteomalacia.
“Perhaps these proteins are critical parts of the phosphate
regulatory pathway because they are found in a genetic form of phosphate
wasting,” Jan de Beur says. Noting that she and her colleagues have
demonstrated that FGF-23 can inhibit phosphate transport in kidney cells, Jan de
Beur adds, “Now we’re putting PHEX together with other upregulated genes,
including FGF-23, to see if it inactivates the molecule that inhibits phosphate
transport in kidney cells.”
The next step would be to infuse the protein into animal models and test whether they reabsorb phosphate. That would be the proof and principle that these genes inhibit phosphate transport.
“It would mean we’ve found the protein responsible for oncogenic osteomalacia, and an important regulator of phosphate in general,” Jan de Beur says. Such findings could possibly lead to therapies to increase phosphate to build weakened bones, or to lower phosphate in patients who retain it, many of whom suffer renal failure.