INCREASED PROLIFERATION OF OSTEOBLASTIC CELLS EXPRESSING THE ACTIVATING G(S)ALPHA MUTATION IN MONOSTOTIC AND POLYOSTOTIC FIBROUS DYSPLASIA

We studied the osteoblastic abnormalities resulting from activating mu tation of the G(s) alpha gene in two patients with McCune-Albright syn drome and one patient with monostotic fibrous dysplasia. Histomorphome tric analysis of dysplastic lesions showed a low number of differentia ted osteoblasts along the bone surface and numerous immature alkaline phosphatase-positive mesenchymal cells actively depositing a woven bon e matrix. Osteoblastic cells isolated from dysplastic bone lesions exp ressed a missense mutation in the G(s) alpha gene in position 201 and shoved increased intracellular basal cyclic adenosine 3',5'-monophosph ate levels compared with normal cells isolated from a noninvolved area in the same patient. Cell proliferation evaluated by DNA synthesis wa s twofold to threefold greater in osteoblastic cells expressing the mu tation compared with normal cells from the same Patient and tvas great er in cells isolated from more severe than less severe fibrotic lesion s. In contrast, the synthesis of osteocalcin, a marker of mature osteo blasts, was lower in osteoblastic cells expressing the G(s) alpha muta tion compared with normal cells from the same patient and teas lower i n cells isolated from severe compared with less severe fibrotic lesion s, indicating that the increased growth in mutated osteoblastic cells was associated with reduced cell differentiation, The results show tha t activating mutation of G(s) alpha in osteoblastic cells lends to con stitutive activation of adenylate cyclase, increased cell proliferatio n, and inappropriate cell differentiation, resulting in overproduction of a disorganized fibrotic bone matrix in polyostotic and monostotic fibrous dysplasia.