Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease

被引:77
作者
Kurihara, Noriyoshi
Hiruma, Yuko
Zhou, Hua
Subler, Mark A.
Dempster, David W.
Singer, Frederick R.
Reddy, Sakamuri V.
Gruber, Helen E.
Windle, Jolene J.
Roodman, G. David
机构
[1] VA Pittsburgh Healthcare Syst, Res & Dev, Pittsburgh, PA 15240 USA
[2] Univ Pittsburgh, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15260 USA
[3] Helen Hayes Hosp, Reg Bone Ctr, W Haverstraw, NY USA
[4] Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA 23284 USA
[5] Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY 10027 USA
[6] John Wayne Canc Inst, Endocrine Bone Dis Program, Santa Monica, CA USA
[7] Med Univ S Carolina, Childrens Res Inst, Dept Pediat, Charleston, SC 29425 USA
[8] Carolinas Med Ctr, Dept Orthopaed Surg, Charlotte, NC 28203 USA
关键词
D O I
10.1172/JCI28267
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 hyper-responsive to receptor activator of NF-kappa B ligand (RANKL) and TNF-alpha. and showed increased NF-kappa B 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.
引用
收藏
页码:133 / 142
页数:10
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