Glucocorticoids decrease interleukin-6 levels and induce mineralization of cultured osteogenic cells from children with fibrous dysplasia.
Fibrous dysplasia (FD) is a progressive bone disease in which abnormal fibroblast proliferation results in the replacement of normal cancellous bone with an immature fibrous tissue that is poorly mineralized. The disease manifests itself in the monostotic form in which only one bone is involved and the polyostotic form in which multiple bones at different sites are affected. The McCune-Albright syndrome is a variation of the polyostotic form in which patients demonstrate a greater extent of bone involvement and a variety of endocrinopathies. Somatic activating mutations in the GNAS gene have been demonstrated in the fibrotic lesions of patients affected with either monostotic or polyostotic FD. The increased cAMP levels caused by the G-protein mutations lead to increased interleukin-6 (IL-6) levels in the affected tissues, resulting in abnormal osteoblast differentiation and increased osteoclastic activity. Utilizing cell culture techniques that have been developed for mammalian bone marrow stromal cells, we have successfully cultured osteogenic stem cells from the affected stroma of 11 FD patients. Cells cultured from patients with polyostotic FD showed a high frequency of the Gsalpha mutation, whereas cells from monostotic FD patients showed a low frequency of the mutation. Both the normal and FD cells displayed the osteogenic phenotype when exposed to medium containing glucocorticoids. Glucocorticoids also caused a dramatic inhibition of IL-6 mRNA and protein levels in osteogenic cells cultured from the FD patients. These findings suggest that chemical alteration of cellular function may lead to new treatment options for patients with FD.
Stanton
R P
RP
Department of Orthopaedics, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, USA.
Hobson
G M
GM
Montgomery
B E
BE
Moses
P A
PA
Smith-Kirwin
S M
SM
Funanage
V L
VL
D000293:Adolescent; D000328:Adult; D001854:Bone Marrow Cells / Q000378:metabolism / Q000648:ultrastructure; D002113:Calcification, Physiologic / Q000187:drug effects*; D002478:Cells, Cultured; D002648:Child; D004252:DNA Mutational Analysis; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005357:Fibrous Dysplasia of Bone / Q000235:genetics / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism / Q000648:ultrastructure
D005938:Glucocorticoids; D015850:Interleukin-6; D003907:Dexamethasone; D019205:GTP-Binding Protein alpha Subunits, Gs; D008775:Methylprednisolone