title: Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease.
abstract: Paget disease is the most exaggerated example of abnormal bone remodeling, with the primary cellular abnormality in the osteoclast. Mutations in the p62 (sequestosome 1) gene occur in one-third of patients with familial Paget disease and in a minority of patients with sporadic Paget disease, with the P392L amino acid substitution being the most commonly observed mutation. However, it is unknown how p62(P392L) mutation contributes to the development of this disease. To determine the effects of p62(P392L) expression on osteoclasts in vitro and in vivo, we introduced either the p62(P392L) or WT p62 gene into normal osteoclast precursors and targeted p62(P392L) expression to the osteoclast lineage in transgenic mice. p62(P392L)-transduced osteoclast precursors were hyperresponsive to receptor activator of NF-kappaB ligand (RANKL) and TNF-alpha and showed increased NF-kappaB signaling but did not demonstrate increased 1,25-(OH)(2)D(3) responsivity, TAF(II)-17 expression, or nuclear number per osteoclast. Mice expressing p62(P392L) developed increased osteoclast numbers and progressive bone loss, but osteoblast numbers were not coordinately increased, as is seen in Paget disease. These results indicate that p62(P392L) expression on osteoclasts is not sufficient to induce the full pagetic phenotype but suggest that p62 mutations cause a predisposition to the development of Paget disease by increasing the sensitivity of osteoclast precursors to osteoclastogenic cytokines.
authors.affiliation: VA Pittsburgh Healthcare System, Research and Development, Pittsburgh, Pennsylvania 15240, USA. kuriharan@upmc.edu
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Kurihara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hiruma
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Mark A
authors.initials: MA
authors.lastname: Subler
authors.forename: David W
authors.initials: DW
authors.lastname: Dempster
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Singer
authors.forename: Sakamuri V
authors.initials: SV
authors.lastname: Reddy
authors.forename: Helen E
authors.initials: HE
authors.lastname: Gruber
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.forename: G David
authors.initials: GD
authors.lastname: Roodman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002117:Calcitriol / Q000502:physiology; D002455:Cell Division; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D011506:Proteins / Q000235:genetics*; D053245:RANK Ligand / Q000502:physiology; D000071456:Sequestosome-1 Protein; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D011506:Proteins; D053245:RANK Ligand; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014409:Tumor Necrosis Factor-alpha; D002117:Calcitriol