The p62 P392L Mutation Linked to Paget's Disease Induces Activation of Human Osteoclasts
The p62 P392L Mutation Linked to Paget's Disease Induces Activation of Human Osteoclasts
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DOI：
10.1210/me.2009-0066
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发表时间：
2009-10-01
影响因子：
--
通讯作者：
Roux, Sophie
中科院分区：
文献类型：
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作者：
Chamoux, Estelle;Couture, Julie;Roux, Sophie
编码p62/SQSTM 1的基因突变已在佩吉特骨病（PDB）中描述，确定p62是破骨细胞信号传导中的重要参与者。我们研究了从健康供体或PDB患者的外周血单核细胞分化的破骨细胞的表型，所有的基因分型为p62泛素相关结构域中存在突变。该队列包括携带或不携带p62 P392 L突变的PDB患者和携带或不携带该突变的健康供体。PDB患者的破骨细胞数量更多，含有更多的细胞核，对细胞凋亡更具抵抗力，并且比正常对照组具有更大的骨吸收能力，无论p62突变是否存在。在PDB破骨细胞中观察到p62表达的强烈增加。来自健康携带者的细胞中p62（P392 L）基因的存在赋予了独特的中间破骨细胞表型。此外，我们报告了两种促进生存的激酶，蛋白激酶C zeta和磷酸肌醇依赖性蛋白激酶1，与p62在对照组和在PDB破骨细胞中加入RANKL之前对NF-κ B配体受体激活剂（RANKL）刺激的反应相关。在来自脐带血单核细胞的转染破骨细胞中，p62 P392 L突变导致激酶蛋白激酶C zeta/lambda和磷酸肌醇依赖性蛋白激酶1的活化增加，沿着NF-κ B B的基础活化，与RANKL刺激无关。这些发现清楚地表明，PDB患者中p62的过表达诱导RANKL激活的途径发生重要变化，并上调破骨细胞功能。此外，最常报道的p62突变，P392 L，肯定有助于过度活跃状态的破骨细胞在PDB。（分子内分泌学23：1668-1680，2009）
Mutations of the gene encoding p62/SQSTM1 have been described in Paget's disease of bone (PDB), identifying p62 as an important player in osteoclast signaling. We investigated the phenotype of osteoclasts differentiated from peripheral blood monocytes obtained from healthy donors or PDB patients, all genotyped for the presence of a mutation in the p62 ubiquitin-associated domain. The cohort included PDB patients carrying or not the p62 P392L mutation and healthy donors carrying or not this mutation. Osteoclasts from PDB patients were more numerous, contained more nuclei, were more resistant to apoptosis, and had a greater ability to resorb bone than their normal counterparts, regardless of whether the p62 mutation was present or not. A strong increase in p62 expression was observed in PDB osteoclasts. The presence of the p62(P392L) gene in cells from healthy carriers conferred a unique, intermediate osteoclast phenotype. In addition, we report that two survival-promoting kinases, protein kinase C zeta and phosphoinositide-dependent protein kinase 1, were associated with p62 in response to receptor activator of NF-kappa B ligand (RANKL) stimulation in controls and before RANKL was added in PDB osteoclasts. In transfected osteoclasts derived from cord blood monocytes, the p62 P392L mutation contributed to increased activation of kinases protein kinase C zeta/lambda and phosphoinositide-dependent protein kinase 1, along with basal activation of NF-kappa B, independently of RANKL stimulation. These findings clearly indicate that the overexpression of p62 in PDB patients induces important shifts in the pathways activated by RANKL and up-regulates osteoclast functions. Moreover, the most-commonly reported p62 mutation, P392L, certainly contributes to the overactive state of osteoclasts in PDB. (Molecular Endocrinology 23: 1668-1680, 2009)