McGill Researcher Identifies Protein Involved in Rare Bone and Tooth Disease


Researchers from McGill University and the Federal University of Sao Paulo (Brazil) have identified a substrate protein involved in the most common form of heritable rickets, known as X-linked hypophosphatemia (XLH). XLH results in soft bones that bend and deform, and tooth abscesses that develop spontaneously because of defective tooth calcification.

Dr. Marc McKee, professor in the faculty of dentistry and the department of anatomy and cell biology at McGill University, along with McGill graduate student Betty Hoac and Dr. Nilana Barros of Sao Paulo, have been able to determine a role for osteopontin—an important bone and tooth protein—in defective skeletal and dental calcification. The research builds upon previous findings in the literature that showed that a mutated PHEX gene is responsible for causing XLH. “Identification of the physiologically-relevant substrate protein for the enzyme PHEX has remained elusive for over 15 years, and now we have shown that the substrate is osteopontin,” says Dr. McKee.

“XLH is caused in part by renal phosphate wasting, which is the urinary loss from the body of phosphate, an important building block of bones and teeth, along with calcium,” explains Dr. McKee. “In pursuing other factors that might contribute to XLH, we used a variety of research methods to show that PHEX enzymatic activity leads to an essentially complete degradation of calcification-inhibiting osteopontin in bone.” Using a mouse model that lacks functional PHEX and which therefore mimics human XLH, the researchers showed that inhibitory osteopontin is retained within the bone to prevent its hardening. It is expected the same mechanism applies to teeth to make the dentin soft and prone to infections and abscesses as seen in XLH.

These findings open the way to the development of a PHEX-replacement therapy. The results of the research, which received funding from CIHR and FAPESP (Brazil), are published in the March 2013 issue of the Journal of Bone and Mineral Research.

The XLH Network has developed guidance documents for both dentists and dental patients to better understand, recognize and treat XLH.

XLH is a rare disease that affects about one person in 20 000. Within the framework of international Rare Disease Day, more than 60 countries and regions worldwide will be holding awareness-raising activities on February 28, 2013. To learn more about the events taking place in Canada, visit the Rare Disease Day website.