A major goal of the Skeletal Clinical Studies program is to elucidate the role of osteogenic cells in the generation of a variety of skeletal dysplasias. It was found that the metabolic activity of bone-forming cells is altered by a number of known mutations. In fibrous dysplasia of bone (FD) and in McCune-Albright Syndrome (MAS) which presents with severe fibrous dysplasia, there are missense mutations of the G protein, Gs alpha, leading to overproduction of cAMP. It was found that this protein is dramatically upregulated as bone marrow stromal cells (BMSCs) mature into osteoblasts, and the effects of the mutations are manifested by abnormal cell-cell (hyperosteocytic bone), cell-matrix interactions (cellular retraction), and the formation of an abnormal bone matrix. A spectrum of bone lesions associated with such mutations were identified and recognizable as three primary, but distinct, histological patterns. The data emphasize the non-random (site-specific) variability of FD histopathology in patients carrying activating mutations of the Gs alpha gene, and provide additional evidence for the occurrence of Gs alpha mutations in cases of FD other than typical MAS. Using an in vivo transplantation system, it was found that populations containing mutated BMSCs leads to the recapitulation of FD formation in immunocompromised mice, representing a novel model system for determination of the pathophysiology of the disease and development of new therapeutic strategies. Furthermore, the study demonstrated the need for both normal and mutated cells (somatic mosaic) for formation of an FD lesion. Another goal was to examine the ability of ex vivo BMSCs, to regenerate normal bone tissue. Full thickness osseous defects (5 mm) were prepared in the cranium of immunocompromised mice and were treated with gelatin sponges containing murine alloplastic bone marrow stromal cells. Cultured bone marrow stromal cells transplanted within gelatin sponges resulted in osteogenesis that repaired greater than 99.0% ' 2.20% of the original surgical defect within two weeks. From these studies, several clinical protocols for the study and treatment of patients with FD, and for bone regeneration have been approved (or will be approved in the near future).
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