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Editor—Fibrous dysplasia of bone is a sporadic developmental condition characterised by intense marrow fibrosis and increased rates of bone turnover. Mutations of the gene encoding the α subunit of the stimulatory guanine nucleotide binding protein (GNAS1) linked to adenylate cyclase have been described in bone cells from patients with McCune-Albright syndrome.1 2 The mutations identified are missense point mutations within exon 8 that result in a substitution of histidine or cysteine for arginine at amino acid 201 (R201H or R201C). Both mutations lead to the constitutive activation of adenylate cyclase resulting in increased signalling through the cyclic AMP (cAMP) pathway. While the cause of fibrous dysplasia of bone has been clarified by the discovery of GNAS1mutations in bone cells, the pathogenesis of the characteristic finding of bone lesions is as yet unclear. We have performed molecular analysis of cultured cells isolated from the periosteum and hypertrophic endosteal membrane of the identical area in a patient with severe polyostotic fibrous dysplasia associated with a degenerate cystic bone change.
The patient was an 11 year old Japanese boy who had severe polyostotic fibrous dysplasia involving the upper and lower extremities, ribs, vertebral bodies, pelvis, and skull. He felt unbearable pain in his right upper arm without history of trauma. Radiographic examination showed a “blow out” expansion of a cystic lesion with only faintly visible cortical margins (fig 1). An open biopsy was performed, showing a thin shell of bone, a cavity filled with yellow serous fluid, and endosteal hypertrophic fibrous membrane. Histological examination showed that the bone matrix was thin and poorly mineralised and there was prominent mesenchymal cell proliferation with numerous secretory granules in the endosteal fibrous or granulomatous capsule.3
Samples of the endosteal fibrous capsule and the periosteum were cultured in Dulbecco’s modified Eagle medium (DMEM) (Gibco BRL) supplemented with 10% fetal calf serum and antibiotics. Genomic DNA was extracted and analysed for mutations ofGNAS1 exon 8 by PCR coupled with direct sequencing. The GNAS1 exon 8 PCR amplicon derived from the cultured endosteal fibrous membrane showed heterozygosity for a C to T transition within codon 201, resulting in a substitution of cysteine for arginine (R201C). On the other hand, normal alleles were observed within GNAS1exon 8 in the cells from the periosteum.
Activating missense mutations of GNAS1leading to overactivity of adenylyl cyclase have been identified in bone samples from patients with McCune-Albright syndrome and monostotic fibrous dysplasia,4-6 but the mechanism leading to the specific development of fibrous dysplasia in bone has not been well elucidated. It was suggested that Gsα is normally highly upregulated in the transition from pre-osteoblasts to fully mature osteoblasts.7 A probable consequence of the adenylate cyclase activating mutations of GNAS1in bone lesions of fibrous dysplasia is the increased expression of the c-fos proto-oncogene and its proteins,8 and the activation of the transcription factor AP-1.9 Further investigations showed evidence of increased interleukin (IL)-6 production by mutant cells.10 11 The presence of the AP-1 binding site in the promotor regions of theIL-6 gene indicates the mechanisms by which IL-6 production is mediated and the biological response to IL-6 is an increased number of osteoclasts in the lesions.12 These findings suggest that the activating mutations ofGNAS1 in osteoblastic cells produce constitutive activation of adenylate cyclase, increased cell proliferation, and inappropriate cell differentiation, which results in a disorganised fibrotic bone matrix in fibrous dysplasia.13 In addition, increased osteoclasts may promote bone resorption resulting in extensive invasion of fibrous dysplasia.
Activating GNAS1 mutations are thought to occur postzygotically leading to a somatic mosaic state. In endocrine organs from patients with McCune-Albright syndrome, the highest proportion of mutated cells was observed in abnormal tissues, but was very low in histologically normal parts of the same organ.1 Bianco et al 14 cultured progenitor cells of the bone marrow stroma involved in fibrous dysplasia and showed two different genotypes in single fibrous dysplastic lesions: marrow stromal cells containing two normal alleles and those containing a normal allele and an allele with an activating mutation. Here we delineated for the first time a molecular difference between the periosteum and the endosteum of the identical affected area in a patient with polyostotic fibrous dysplasia, although these findings might be specific for the present patient rather than generalised.
The normal periosteal cells in the present case probably stimulate appositional bone formation during bone remodelling, while the mutant cells of the endosteal tissue not only increase in number but also produce an abnormal complement of bone matrix protein. In addition, the mutant cells may stimulate osteoclasts and promote bone resorption. In bone remodelling of the patient, bone resorption and replacement by endosteal fibrous tissue may exceed new bone formation by the periosteum, resulting in an extraordinarily thin cortex. Increased excretion by abnormal endosteal cells may accelerate characteristic deformity of bone expansion.