Study seeks to understand the molecular triggers of bone development

Skeletal dysplasia is the medical term for the bone and cartilage abnormalities that afflict as many as one in 5,000 children.  While dwarfism is the most blatantly visible example, skeletal dysplasia covers a wide spectrum of more than 200 types of cartilage and bone growth anomalies.  The unfortunate hallmarks for children affected are malformations and irregularities that can occur in the size and shape of the skeleton, long bones, spine and head.  

Each variation of this disorder carries its own issues for children and their families. The psychological impact of severe disproportion, coupled with what may be physically debilitating deformities, can be devastating.

Among the skeletal dysplasias treated at St. Louis Children’s Hospital is a rare condition known as proximal femoral focal deficiency (PFFD), which affects approximately one in 50,000 live births. In children with PFFD, the part of the thighbone that is close to the hip is not completely developed, or is shortened, resulting in one leg (or both) being abnormally short and typically bowed.

“The PFFD severity spectrum is large,” says Dr. Matthew Dobbs, associate professor of orthopedic surgery. “A mild condition may require just a lift in one shoe. Children who present with more severe problems may undergo procedures to slow the growth of the unaffected leg. Still other severely affected children may be candidates for mechanical limb lengthening of the affected leg. In the most severe cases, so much bone is missing that amputation and creation of a prosthesis are required.”

At present, the cause of PFFD is not known. A new collaboration between researchers and physicians at Washington University, St. Louis Children’s Hospital, and St. Louis Shriner's Hospital aims to change that. Dr. Fanxin Long, assistant professor of medicine and of developmental biology, is leading a project funded by a grant from the Children’s Discovery Institute to investigate the effect of specific gene mutations on the longitudinal growth of the human skeleton.

Development of embryonic tissue into cartilage and then into bone relies on chemical signaling -- genetic stop and go lights – that turn genes on and off at certain times to achieve normal skeletal growth. Researchers who study the bone development pathway have identified some of these signaling molecules, and have given them colorful names like Indian hedgehog, SHOX and Runx2.

It is known that mutations of the SHOX gene can lead to congenital skeletal dysplasia. “But until recently we haven’t been able to investigate that further because our animal models don’t have the same gene,” said Long. “Luckily, a gene similar in structure and origin to SHOX exists in both humans and mice, and we call it SHOX2. Moreover, mice engineered to lack this SHOX2 gene have severe limb shortening.”

Dr. Long and others believe that SHOX and SHOX2 control skeletal growth through the same mechanism. “So we now have a mouse model for testing our hypotheses that SHOX proteins interact with the Runx2 and Indian Hedgehog, as well as with fibroblast growth factors to regulate skeletal growth,” says Long. The hope is to gain some understanding of how changes in these molecules may halt or limit progress toward normal bone elongation.

A key part of the research project will be to link what is learned in Dr. Long’s laboratory with patients who are affected by proximal femoral focal deficiency (PFFD) or other congenital skeletal dysplasia.

The similarities between the mouse and human genes suggest that mutations in the human SHOX2 gene may play a key role in PFFD. This link will be evaluated by analyzing the DNA of patient volunteers affected with PFFD to look for relevant gene mutations.

Clinical support for the project will be provided by these physicians and researchers: Dr. Christina Gurnett, assistant professor of neurology; Dr. Matthew Dobbs, associate professor of orthopedic surgery; Dr. Dorothy Grange, associate professor of pediatrics and Dr. Michale Whyte, professor of medicine, director for metabolic bone disease and molecular research at St. Louis Shriner’s Hospital. Dr. David Ornitz, alumni endowed professor, and head of Department of Developmental Biology, will collaborate on the basic science.

Dr. Long cautions that interventions to reduce or eliminate these types of skeletal abnormalities are still far from being realized. “But with the support of the Children’s Discovery Institute, we will be able to clarify some of the biological mechanisms that underlie these conditions. And that will bring us a bit closer to the goal.”