FIBROUS DYSPLASIA OF BONE IN THE MCCUNE-ALBRIGHT SYNDROME - ABNORMALITIES IN BONE-FORMATION

In addition to cafe-au-lait pigmentation patterns and hyperendocrinopa thies, fibrous dysplasia of bone is a major finding in the McCune-Albr ight syndrome, Activating missense mutations of the Gs alpha gene lead ing to overactivity of adenylyl cyclase have been identified in patien ts with McCune-Albright syndrome, but the mechanism leading to the spe cific development of fibrous dysplasia in bone has not been elucidated , By means of specific peptide antisera and reverse transcriptase poly merase chain reaction in situ hybridization, we show that expression o f Gs alpha and its mRNA is critically up-regulated during maturation o f precursor osteogenic cells to normal osteoblast cells and that this pattern of expression is retained in fibrous dysplasia, A functional c haracterization of fibrous dysplastic tissues revealed that the fibrot ic areas consist, in fact, of an excess of cells with phenotypic featu res of pre-osteogenic cells, whereas the lesional bone formed de novo within fibrotic areas represents the biosynthetic output of mature but abnormal osteoblasts. These cells are noted for peculiar changes in c ell shape and interaction with matrix, which were mimicked in vitro by the effects of excess exogenous cAMP on human osteogenic cells, Osteo blasts involved with the de novo deposition of lesional bone in fibrou s dysplasia produce a bone matrix enriched in certain anti-adhesion mo lecules (versican and osteonectin), and poor in the pro-adhesive molec ules osteopontin and bone sialoprotein, which is in contrast to the hi gh levels of these two proteins found in normal de novo bone, Our data indicate the need to reinterpret fibrous dysplasia of bone as a disea se of cells in the osteogenic Lineage, related to the effects of exces s cAMP on bone cell function. They further suggest that a critical, ph ysiological, maturation-related regulation of Gs alpha levels makes ce lls in the osteogenic lineage a natural target for the effects of muta tions Ln the Gs alpha gene and may provide a clue as to why bone itsel f is affected in this somatic, mutation-dependent disease.