When we think of rickets, the bone-softening disorder that causes short stature and bowing deformations of the legs, we’re likely to imagine that the disease is a relic of the distant past. But rickets is still very much with us, says Thomas O. Carpenter, M.D., professor of pediatrics and a leading rickets researcher.

Carpenter first encountered rickets in the 1970s as a resident at Children’s Hospital at the University of Alabama in Birmingham. Most of the cases he saw were nutritional in origin—a lack of calcium and vitamin D in the diet are the two main causes of rickets and have accounted for a rising incidence of the disease over the past 20 years.

But Carpenter was particularly intrigued by children with X-linked hypophosphatemia, or XLH, an inherited form of the disease caused by a mutation on the X chromosome.

As the disease’s name implies, these children have very low levels of phosphate because they excrete too much of this mineral in their urine; however, unlike children with dietary rickets, XLH patients have normal levels of both calcium and vitamin D. Carpenter, who directs the Yale Center for X-Linked Hypophosphatemia (YC-XLH), says that 30 years ago he found these contradictory lab findings “baffling.”

However, recent studies have revealed a previously unknown system governing mineral balance and bone growth, and biomedical science is on the cusp of a new understanding of XLH, Carpenter says. With the help of a $5,000,000 Centers of Research Translation (CORT) grant, one of four awarded nationwide last fall by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, he and YC-XLH co-director Karl L. Insogna, M.D., professor of medicine, are using this new knowledge to embark on an ambitious, multipronged scientific attack on XLH, the most common inherited form of rickets.

“Over the past 10 years, the science really opened up and revealed an entirely novel mechanism of phosphate regulation,” Carpenter says. In 1995, the mutated gene that causes XLH was identified as PHEX; this discovery has allowed scientists to create mouse models of the disease that exhibit a pattern of phosphate depletion, bone deformation and dental abnormalities similar to those seen in human patients.

It was subsequently discovered that a protein known as fibroblast growth factor 23 (FGF23) plays a crucial role in autosomal dominant hypophosphatemic rickets (ADHR), a rare inherited form of the disease that closely resembles XLH. More recently, yet another protein, DMP1, has been shown to be central to a third form of inherited rickets (autosomal recessive hypophosphatemic rickets) that also closely resembles XLH. Most strikingly, the PHEX protein, FGF23 and DMP1 have been found to be most abundantly expressed in the same specialized bone cell, the osteocyte. Carpenter believes that PHEX (an enzyme), DMP1 and FGF23 must all work in the same pathway that is involved in XLH. “This is the most convincing evidence to date,” Carpenter says, “for an intimate connection between skeletal biology and systemic mineral balance in the body.”

The standard treatments for XLH are calcium and phosphate supplements, but the levels of these minerals must be carefully monitored to avoid serious side-effects. Carpenter says that the CORT grant will allow him and his colleagues to advance more precise and effective molecular therapies.

The three main lines of inquiry that comprise the CORT are being pursued with the support of a Research Core facility directed by Caren M. Gundberg, Ph.D., professor of orthopaedics and rehabilitation. Carpenter and Insogna will lead two clinical studies: one will determine what biochemical markers best predict the severity of XLH cases; a second will focus on the role of parathyroid hormone excess in the disease, and will apply a specific therapy to correct this complication of XLH. Marie B. Demay, M.D., associate professor of medicine at Massachusetts General Hospital in Boston, will lead a project exploring her recent finding that phosphate regulates cell death in cartilage cells. Finally, Joseph Schlessinger, Ph.D., the William H. Prusoff Professor and chair of Pharmacology (see related story, “Finding a New Chink in Cancer’s Armor”) will join Veraragavan P. Eswarakumar, Ph.D., newly appointed assistant professor of orthopaedics and rehabilitation, to identify and characterize the cell-surface receptor for FGF23. Based on the FGF23 studies, members of the YC-XLH will develop small molecules to inhibit activation of the receptor and test them in preclinical trials, and, if successful, Phase 1 clinical trials. In addition to the research projects, the YC-XLH has co-sponsored a Bone Seminar Series with the NIH-sponsored Yale Core Center for Musculoskeletal Disorders, and will soon be launching a pilot and feasibility program for further work in this related field.

To complement his work on XLH, Carpenter continues to study and treat nutritional rickets in inner-city New Haven children with the help of a 3-year, $844,000 grant he received in 2005 from the Gerber Foundation.

“The newly discovered mechanisms by which our bodies regulate phosphate are very exciting, and have broad implications in human biology,” says Carpenter. “We have learned so much from the patients who have contended with so many long-term consequences of XLH that it is only fitting that we may soon be able to apply these discoveries to new therapies that should significantly improve their quality of life.”