title: A mutation affecting the latency-associated peptide of TGFbeta1 in Camurati-Engelmann disease enhances osteoclast formation in vitro.
abstract: Camurati-Engelmann disease (CED) is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. CED is caused by various missense mutations in the TGFB1 gene that encodes TGFbeta1, the most common of which is an arginine-cysteine amino acid change at codon 218 (R218C) in the latency-associated peptide domain of TGFbeta1. We studied osteoclast formation in vitro from peripheral blood mononuclear cells obtained from three related CED patients harboring the R218C mutation, in comparison with one family-based and several unrelated controls. Osteoclast formation was enhanced approximately 5-fold (P < 0.001) and bone resorption approximately 10-fold (P < 0.001) in CED patients, and the increase in osteoclast formation was inhibited by soluble TGFbeta type II receptor. Total serum TGFbeta1 levels were similar in affected and unaffected subjects, but concentrations of active TGFbeta1 in conditioned medium of osteoclast cultures was higher in the three CED patients than in the unaffected family member. We concluded that the R218C mutation increases TGFbeta1 bioactivity and enhances osteoclast formation in vitro. The activation of osteoclast activity noted here is consistent with clinical reports that have shown biochemical evidence of increased bone resorption as well as bone formation in CED.
authors.affiliation: Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom.
authors.forename: Neil W A
authors.initials: NW
authors.lastname: McGowan
authors.forename: Heather
authors.initials: H
authors.lastname: MacPherson
authors.forename: Katrien
authors.initials: K
authors.lastname: Janssens
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.forename: Julie C
authors.initials: JC
authors.lastname: Frith
authors.forename: William D
authors.initials: WD
authors.lastname: Fraser
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Miep H
authors.initials: MH
authors.lastname: Helfrich
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D003966:Camurati-Engelmann Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000166:cytology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology*; D017354:Point Mutation; D053245:RANK Ligand; D011859:Radiography; D053246:Receptor Activator of Nuclear Factor-kappa B; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology; D053773:Transforming Growth Factor beta1
chemical_list: D000906:Antibodies; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C508960:TGFB1 protein, human; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016173:Macrophage Colony-Stimulating Factor