The Skeletal Clinical Studies program has established three clinical protocols (98-D-0145, 98-D-0146, 99-D-003) and participates in a fourth (97-DK-0057) for the study and treatment of fibrous dysplasia of bone (FD) and the McCune-Albright Syndrome (MAS). FD is found in a broad range of severities, ranging from monostotic (single bone) to polyostotic (many bones) and often in association with the MAS, which in addition to FD has multiple endocrinopathies and skin hyperpigmentation. MAS is known to arise from a post-zygotic mutation in the GNAS1 gene (R201C and R201H). An in-depth histological and molecular study of FD lesions revealed a great deal of variation in the nature of the lesions, and aided by the development of a novel assay by Dr. Larry Fisher, all of the patients were found to have GNAS1 mutated cells. In addition, we also identified a novel R201G mutation in one of our patients. These results indicate that GNAS1 mutations result in a broad spectrum of bone lesions even outside of the context of MAS, and that new therapies may have a broader impact that previously realized. Although it has been known since the 1960's that bone marrow stroma contains a population of cells that have the ability to form bone, cartilage, myleosupportive stroma, adipocytes and perhaps other connective tissues, it is only recently their utilization for bone regeneration has been fully realized, and the program has developed procedures whereby ex vivo expanded bone marrow stromal cells could be used in tissue regeneration. Defects were created in the skulls of mice that were of sufficient size that they would never spontaneously heal. When these defects were filled with a composite of ex vivo expanded bone marrow stromal cells and an appropriate carrier, bone and marrow were completely regenerated. These studies have served as the basis for development of procedures for use in humans with similar, non-healing bone defects. An application has been submitted to the FDA, and it is hoped that clinical trials will begin in the very near future.
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| Applbaum, Arthur Isak; Tilburt, Jon C; Collins, Michael T et al. (2008) A family's request for complementary medicine after patient brain death. JAMA 299:2188-93 |
| Celi, Francesco S; Coppotelli, Giuseppe; Chidakel, Aaron et al. (2008) The role of type 1 and type 2 5'-deiodinase in the pathophysiology of the 3,5,3'-triiodothyronine toxicosis of McCune-Albright syndrome. J Clin Endocrinol Metab 93:2383-9 |
| Kuznetsov, Sergei A; Cherman, Natasha; Riminucci, Mara et al. (2008) Age-dependent demise of GNAS-mutated skeletal stem cells and ""normalization"" of fibrous dysplasia of bone. J Bone Miner Res 23:1731-40 |
| Dumitrescu, Claudia E; Collins, Michael T (2008) McCune-Albright syndrome. Orphanet J Rare Dis 3:12 |
| Michienzi, Stefano; Cherman, Natasha; Holmbeck, Kenn et al. (2007) GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs alpha. Hum Mol Genet 16:1921-30 |
| Khosravi, Azarmindokht; Cutler, Carolee M; Kelly, Marilyn H et al. (2007) Determination of the elimination half-life of fibroblast growth factor-23. J Clin Endocrinol Metab 92:2374-7 |
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