p62 Ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-κB ligand-induced osteoclast formation -: A new insight into the pathogenesis of Paget's disease of bone
p62 Ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-κB ligand-induced osteoclast formation -: A new insight into the pathogenesis of Paget's disease of bone
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DOI：
10.2353/ajpath.2006.050960
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发表时间：
2006-08-01
影响因子：
6
通讯作者：
Xu, Jiake
中科院分区：
文献类型：
--
作者：
Yip, Kirk H. M.;Feng, Haotian;Xu, Jiake
骨佩吉特病（PDB）是一种以巨大破骨细胞、骨破坏增强和骨形成不规则为特征的使人衰弱的骨疾病。最近，已在PDB患者中检测到SQSTM 1（也称为p62）的突变，所有突变均导致泛素结合相关（乌巴）结构域的功能丧失或截短/缺失。我们假设p62基因突变导致乌巴结构域缺失或提前终止，这是PDB相关骨形成和骨吸收增加的原因。值得注意的是，在RAW 264.7破骨细胞生成系统中，与表达野生型p62（p62 WT）或对照载体的细胞相比，p62 URN结构域缺失突变体（p62 Delta乌巴）的过表达显著增强了体外破骨细胞生成。p62 δ乌巴的过表达增强了异常大的多核破骨细胞的形成和骨的吸收，使人联想到PDB。与破骨细胞生成的增强一致，p62 Δ乌巴的过表达增强了核因子-κ B配体的受体激活剂诱导的核因子-κ B、NFAT和ERK磷酸化的活化。此外，如通过共聚焦显微镜所确定的，p62乌巴结构域的缺失损害了蛋白酶体区室中p62与TRAF 6的关联。这些结果表明，乌巴结构域编码核因子-κ受体激活剂B配体诱导的破骨细胞形成和骨吸收所需的基本调控元件，可能与PD B的进展直接相关。
Paget's disease of bone (PDB) is a debilitating bone disorder characterized by giant osteoclasts, enhanced bone destruction, and irregular bone formation. Recently, mutations in SQSTM1 (also known as p62) have been detected in PDB sufferers, with all mutations resulting in either loss of function or truncation/deletion of the ubiquitin binding-associated (UBA) domain. We hypothesized that mutation in the p62 gene resulting in either deletion or premature termination of the UBA domain accounts for the elevated osteoclastic formation and bone resorption associated with PDB. Remarkably, overexpression of the p62 URN domain deletion mutant (p62 Delta UBA) significantly enhanced osteoclastogenesis in vitro compared to cells expressing either wild-type p62 (p62WT) or a control vector in a RAW264.7 osteoclastogenic system. Overexpression of p62 Delta UBA potentiated the formation of abnormally large multinucleated osteoclasts and resorption of bone, reminiscent of PDB. Consistent with the enhancement of osteoclastogenesis, overexpression of p62 Delta UBA potentiated receptor activator of nuclear factor-kappa B ligand-induced activation of nuclear factor-kappa B, NFAT, and ERK phosphorylation. Furthermore, as determined by confocal microscopy, deletion of the p62 UBA domain impaired the association of p62 with TRAF6 in the proteasomal compartment. These results suggest that the UBA domain encodes essential regulatory elements required for receptor activator of nuclear factor-kappa B figand-induced osteoclast formation and bone resorption that may be directly associated with the progression of PDB.