Fibrous Dysplasia: A roadmap to treatment enabled by discovery of unpredicted mechanisms in first-in-class mouse models

Fibrous dysplasia of bone (polyostotic fibrous dysplasia, McCune-Albright syndrome) is a genetic disease that affects bone and other organs, causing disorders of endocrine glands, skin, liver, heart, muscle besides the bone disease. The bone disease is the most severe and least treatable aspect of the disease, hence it is in need of research to find a cure. One, few, many or all bones can be affected. Beginning in childhood, the affected bones deform, fracture spontaneously or with minimal trauma, and ache. Disfigurement, deformity, crippling, wheelchair confinement, and in rare cases, loss of eyesight or hearing and even death, ensue. Affected bones are soft and fragile. This is due to their reduced content in calcium phosphate (osteomalacia), and constant excess resorption by specialized cells (osteolysis). Osteomalacia causes deformity, and osteomalacia and osteolysis cause fractures and pain. In addition, the bone marrow that produces blood cells inside the bones, is lost to an abnormal scar-like tissue (fibrosis). These changes emanate from the genetic defect, which consists in a mutation in a protein (called Gs-alpha) that allows cells in all tissues and organs to respond to hormones and nerves. How this gene defect makes bad bone cells and how these make bad bone is crucial to develop a therapy. Today, FD has no cure. Surgery is difficult and risky and cannot help patients with extensive disease, All drugs in use cannot halt, slower or reverse the bone disease. We have now put the disease gene in mice, creating mice with fibrous dysplasia, for the first time in the world, and discovered unsuspected ways of action of the bad gene. Using these models and more that are needed and we will create, we want to understand why bone becomes soft and fragile, and tackle the causes of pain, deformity and fracture in FD. We also want to test in our mice one specific treatment as suggested by our previous studies, to inhibit osteolysis using specific antibodies.