The genetics of FD
The genetic abnormality is an active mutation of GNAS, the gene encoding the subunit of the stimulatory G protein (Gs) on the 20q13 chromosome. These active GNAS mutations have been detected in skeletal lesions of patients with MAS (4) or isolated dysplasia, which is mono or polyostotic (5). The mutated GNAS allele gives rise to a substitution of a single unit in the CGT codon of the exon 8 encoding for the mutated protein in which arginine 201 (R201) is replaced by histidine (R201H, G>A), cysteine (R201C, C>T) or more rarely by another amino acid (R201S, C>A; R201G, C>G) (6,7).
The R201 GNAS mutations are post-zygotic, generating a mosaic somatic state, in which, during embryonic development, mutated cells coexist with normal cells in the affected bone segments, where FD will be present at birth. As FD is not transmissible this leads to a mutated gene with a lethal characteristic that would result in a totally mutated organism (8), which indicates that each patient represents a new mutation event.
The GNAS mutations are associated with a gain in function, which increases the production activity of the mutated gene. Gs is a trimeric protein coupled to the 7 transmembrane domain receptors, which release a specific response in target cells through a cAMP pathway. The subunit plays a critical role in the regulation of Gs activity. Through ligand-receptor bonding, Gsa exchanges GDP for GDP, which dissociates the b and g subunits and stimulates adenylate-cyclase, which generates cAMP. This leads to a sequence of molecular events, activating the target genes. Through its intrinsic phosphatase activity, the subunit quickly releases a phosphate from GTP after stimulation, which terminates the system, leaving it available for new stimulation. The replacement of R201 in the GSA protein reduces its phosphatase activity by 30 to 100 times (10), and leads to an increase in cAMP in mutated cells, independent of the bonding of the ligand.
Pathogenicity and anatomical pathology: FD is a disease of the stem cells and osteoblasts
Knowledge of the osteogenic nature of the fibrous marrow of FD has led to certain widespread misconceptions about the metaplastic nature of dysplasic bone (3). The fibroblast cells filling the bone marrow express early osteogenic markers, such as alkaline phopshatase, whilst the cells producing the bone matrix along the length of the shaft express late osteogenic markers, such as osteocalcin and osteonectin (3). The in vivo phenotype of FD cells indicate their authentic osseous nature and reveal the role of the dependant signalling pathway of Gsa and cAMP in normal skeletal differentiation. Bone stem cells and their precursors are usually found in the non-hematopoietic (stromal) compartment of the bone marrow, and are the source of different cell phenotypes (osteoblasts, adipocytes and hematopoietic cells) (11). The stem cells carrying the GNAS mutation differentiate in an atypical way and are not capable of producing hematopoietic cells and adipocytes.
The over regulation of the GSa gene during the latter stages of osteoblast differentiation amplify the influence of the GNAS mutations on the mature osteogenic cells (3). In this context, the microscopic appearance of FD, previously considered as non specific, or even artifactual, can be considered as a net expression of the excess cAMP in the mature osteoblast cells. In FD, osteoforming cells are characterised by a retracted form, stellate (rendering it overlookable, rather than absent as was once thought). This deterioration as a result of changes to the cytoskeleton, dependent on cAMP, is easily reproducible in vitro (3). The retracted cells are intermittently bound to the perpendicular collagen fibres of the bone surfaces (Sharpey’s fibres), probably due to the forces exerted by the cytoplasmic retraction of the osteoblast cells. These two histological mutations are the essential points of FD lesions, regardless of the skeletal region or the clinical context. (13). FD is a disease in which the biology of the bone matrix is strongly affected. Expression of non-collagen proteins by the osteoblasts is not in equilibrium (3), and seriously affects the biochemical and structural quality of the bone matrix. The increase in expression of enzymes involved in the degradation of collagen in the mutated cells is likely to be responsible for the accelerated turnover of newly deposited osteoid (14). Recently a severely under mineralised bone was considered as a major determinant in fractures and deformities, and thus of the morbidity in the majority of patients (15). This mineralisation defect is the result of the phosphaturic factor FGF-23 (16). The serum concentrations of FGF-23 were high in a sub-group of patients with phosphate diabetes and severe mineralisation problems from dysplasic lesions. FGF-23 is usually expressed in osteogenic cells. FGF-23 expression continues in the mutated cells, at a comparable rate to normal, at a cellular level. Increase in FGF-23 serum concentrations in patients affected by FD reflects the number of osteogenic cells accumulated in the dysplasic tissue, rather than an increase in the synthesis in each cell (15). The biological effects of the GNAS mutation and the stimulation of osteogenic cells through excess cAMP do not account for all bone formation abnormalities. An excess of osteoclasts is often found in many – although not all – FD lesions, with histological characteristics close to those of hyperparathyroidism. The tunnelling resorption, that being inside the bone shafts, and groups of solid osteoclasts (resembling mini brown tumours) often characterise FD lesions (17). In addition, resorption of normal bone is visible at the junction with normal bone, explaining the growth of the lesion. This appears to be linked, at least in part, to the increase in IL-6 expression in the mutated cells (21).
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Created: 09 june 2010