FIBROUS DYSPLASIA: PATHOGENESIS &
Author: Sanketh DS, MDS
Fibrous dysplasia is a tumor like developmental condition, characterised by proliferation of abnormal cellular fibrous connective tissue with irregular trabecular bone replacing the normal medullary bone. This condition occurs due to a mutation in the GNAS (Guanine nucleotide-binding protein,α stimulating activity polypeptide) gene, encoding for the α subunit of G protein. Fibrous dysplasia affects/involves one bone (monostotic) or multiple bones (polyostotic), sometimes together with endocrine abnormalities and abnormal pigmentation.
G proteins are specialised proteins which can bind to nucleotides GDP and GTP. G proteins associated with G protein coupled receptors have 3 subunits – α, β and γ. In the absence of a signal from a ligand, GDP attaches to the α subunit. In the active form, i.e when a ligand binds to a G protein coupled receptor, there is an exchange of GDP for GTP. This GTP is utilised by the α-subunit of the G protein to activate adenylyl cyclase which in turn produces cyclic AMP (cAMP). Cyclic AMP activates protein kinase A which leads to phosphorylation of the target molecules. Normally, the α subunit of the G protein has an intrinsic GTPase activity leading to deactivation of adenylyl cyclase and a break down of the cAMP. But in fibrous dysplasia, GTPase activity in the stimulatory α subunit (Gsα) of the G protein is affected by mutation of the GNAS gene. This leads to continuous stimulation of adenylyl cyclase to produce increased cAMP leading to increased activity of the respective cells/tissues that are stimulated by cAMP.
How does this mutation affect cells and cause the disease?
Increased cAMP, could result in:
1. An abnormal differentiation of the marrow stromal cells to an immature osteoblast and hyper-proliferation of these immature osteoblasts.
2. Alteration of bone matrix proteins resulting in production of abnormal/immature bone.
3. Activation of c-Fos to stimulate the production of bone resorbing cytokines like IL-6 and IL-11.
4. Abnormal pigmentation(café au lait spots) due to an over-production of enzyme tyrosinase.
5. Various endocrinopathies due to hyperplasia and excessive function of different endocrine cell types.
If these mutations occur during early embryonic development affecting pluripotent stem cells, it could affect multiple cell types like osteoblasts, melanocytes and endocrine cells, resulting in polyostotic fibrous dysplasia or McCune Albright syndrome.
However, if the mutations occur in a later stage of embryonic development, it may cause a more restricted pathology, i.e it may affect only a single cell type and if the cell type happens to be an osteo-progenitor, then it may result in a monostotic fibrous dysplasia.
It primarily consists of a slight to moderately cellular, fibrous connective tissue stroma with areas of immature trabeculae of bone. The trabecuale of bone are scattered throughout the lesion with no definite pattern, are thin, “c” shaped and resemble Chinese characters. Osteoblastic rimming is usually absent or minimal but may seldom be present. In the later stages, the immature woven bone may become mature lamellar bone. At the periphery, the lesional bone may fuse with the normal bone.
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