Human Bone Disorder Reproduced In Mice

April 15, 1998

For the first time, scientists have re-created a unique human bone disease in a laboratory animal model. An international team of researchers at the National Institutes of Health and in Italy were able to remove cells from the bone marrow of patients with a genetic bone disorder, transplant the cells into mice, and grow human bone with the same type of abnormalities seen in the patients. The technique holds promise for creating animal models to study many forms of human bone disease, with the hope of discovering the underlying causes and developing novel treatments.

The success of the procedure, reported in the April 15th issue of The Journal of Clinical Investigation, lies in the special characteristics of cells in the bone marrow called stromal cells. The stromal cells have the unique ability to develop into a variety of tissues, including bone, cartilage, and the tissue framework that supports blood formation.

In previous studies, Dr. Pamela Gehron Robey and colleagues at the National Institute of Dental Research (NIDR) perfected a technique for using stromal cells to grow normal human bone in mice. Stromal cells taken from healthy human donors were grown in the laboratory, mixed with ceramic particles, then transplanted under the skin of immune-compromised mice, where they formed a capsule of new bone. The ceramic chips provided structural support for bone growth. The result was a replica of normal bone, consisting of areas of new bone formation surrounding a cavity of healthy marrow that has the cellular infrastructure needed to grow blood cells.

Dr. Gehron Robey, chief of NIDR's Craniofacial and Skeletal Diseases Branch, and Dr. Paolo Bianco, Professor of Pathology at the University of L'Aquila, Italy, coordinated an international research effort to adapt the principle of this technique to develop an animal model for a genetic disorder called McCune-Albright syndrome (MAS) starting from abnormal, mutant stromal cells. The disorder is characterized by scattered areas of weak and deformed bone, patches of abnormal skin pigmentation, and hormonal irregularities, such as precocious puberty. MAS is caused by a mutation in a key cell-signaling molecule called Gs alpha. Interestingly, the mutation takes place after the egg is fertilized and cell division begins, so that only certain cells carry the defect. Some of these cells eventually end up at sites that form parts of the skeleton of the face and limbs, areas of the skin, and tissue components of various endocrine glands.

The crippling bone disturbances were of particular interest to Drs. Bianco and Gehron Robey. MAS patients have regions of bone in which normal marrow has been replaced by functionless fibrous tissue that is interspersed with fragments of weak, poorly formed bone. These areas of bone can be extremely painful and easily broken, and cause severe consequences, including pathological fractures, impairment of limb function, facial and limb deformities, and compressive damage of sensory nerves resulting in blindness or deafness. When the investigators removed stromal cells from marrow lesions in MAS patients, grew them in the laboratory and transplanted the cell-ceramic mix into mice, abnormal human bone formed at the site of transplantation. The transplant consisted of fibrous tissue that did not support blood formation, and contained only thin layers of bone-a replica of the condition in MAS patients.

The mouse model developed by Bianco and Gehron Robey has uncovered another peculiarity of MAS-that mutant and normal cells must both be present in order to form defective bone. This finding concurs with the long-held belief that the MAS mutation is lethal if it occurs before fertilization (in the egg or sperm). In this case, the mutation would affect all cells in the embryo and lead to early embryo death. The investigators felt that the same principle might apply to individual lesions in MAS patients. If only mutant cells were present at a particular site, they might not survive long enough to form even abnormal tissue.

When the investigators examined stromal cells from marrow in MAS patients, they found that the lesions are, in fact, a mixture of normal and mutant cells. When they separated the normal and mutant cells in the laboratory, they were able to reproduce diseased bone only when a mixture of both cell types was transplanted into mice. Mutant cells alone did not survive to produce bone of any kind. It is proposed that the two cell types may link together, either physically or through signaling molecules, to alter normal bone metabolism.

Bianco and Gehron Robey hope to use the animal model to develop novel, effective therapies for the bone lesions of McCune-Albright syndrome, currently a major therapeutic challenge. They also plan to use the same basic approach to develop models for other serious bone disorders.

Working with Drs. Gehron Robey and Bianco on the study were Dr. Mara Riminucci (a former fellow of NIDR) from the University of L'Aquila, Italy (supported in part, along with Dr Bianco, by Telethon Italy), Drs. Sergei Kuznetsov and Larry Fisher from the NIDR, and Dr. Allen Spiegel from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK).

The NIDR, one of the National Institutes of Health located in Bethesda, Maryland, is the nation's leading supporter of research in dental, oral, and craniofacial health. NIDDK is also one of the National Institutes of Health.

NIH/National Institute of Dental and Craniofacial Research

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