The Skeletal Clinical Studies program has continued to focus on two aspects: the role of BMSSCs in skeletal disease, and the use of BMSSCs for tissue regeneration. Patient accrual is continuing in four clinical protocols (97-DK-0055, 98-D-0145, 98-D-0146, 00-D-0183) for the study and treatment of fibrous dysplasia of bone (FD) and the McCune-Albright Syndrome (MAS), which arise from a post-zygotic mutation in the GNAS1 gene (R201C and R201H). We have previously noted that there is a great deal of variability in the histological appearance of FD lesions taken from different patients, and hypothesized that some of these changes may be related to the metabolic status of the patient. Histology, histomorphometry, and quantitative back-scattered electron imaging analysis demonstrated a marked excess of unmineralized osteoid (osteomalacia) with a negative correlation between osteoid thickness in lesional bone and renal tubular phosphate reabsorption, but not for unaffected bone from the same patient. Increased bone resorption was variable in lesional bone, and clearly correlated with serum levels of PTH. Hyperparathyroidism-related histological changes were observed in FD bone, but not in the unaffected bone, of patients with elevated serum PTH. Our data indicate that osteomalacic and hyperparathyroid changes, which emanate from distinct metabolic derangements (which superimpose on the local effects of GNAS1 mutations in bone), influence in turn the severity and type of skeletal morbidity in FD. FD frequently involves the anterior base of the cranium and results in encasement of the optic-nerve canals, and it has been assumed that such encasement leads to constriction and eventual blindness. We studied patients with FD of the lesser wing of the sphenoid bone and found that in 73% of the optic canals, there was complete encasement. In all but two of the patients, the results of neuro-ophthalmologic examination were normal. In the two patients with monocular visual impairment, the areas of the optic canals were similar on the normal and abnormal sides. Encasement of the optic canal by FD bone caused ~18 % narrowing of the canal, but that in itself does not result in visual loss. Therefore, prophylactic decompression of the optic nerve does not appear to be indicated on the basis of the presence of FD on diagnostic images alone, since it does not correlate with visual loss. Finally, FD is also frequently found in the maxilla and mandible, but its effects on dental tissues and implications for dental care have not been well delineated. We characterized dental features associated with maxillo-mandibular FD and reaction of affected bones to routine dental therapy. While patients with craniofacial FD present with a higher incidence of caries and dental malformations, they did not require special dental management and were able to undergo routine dental care. The group is also progressing towards another IND application to the FDA for the use of ex vivo expanded bone marrow stromal stem cells to be used in bone regeneration in the context of fibrous dysplastic lesions.
| Robinson, Cemre; Estrada, Andrea; Zaheer, Atif et al. (2018) Clinical and Radiographic Gastrointestinal Abnormalities in McCune-Albright Syndrome. J Clin Endocrinol Metab 103:4293-4303 |
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| Theman, Todd A; Collins, Michael T; Dempster, David W et al. (2009) PTH(1-34) replacement therapy in a child with hypoparathyroidism caused by a sporadic calcium receptor mutation. J Bone Miner Res 24:964-73 |
| 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 |
| Kelly, M H; Brillante, B; Collins, M T (2008) Pain in fibrous dysplasia of bone: age-related changes and the anatomical distribution of skeletal lesions. Osteoporos Int 19:57-63 |
| 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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