A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment
A SQSTM1/p62 mutation linked to Paget's disease increases the osteoclastogenic potential of the bone microenvironment
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DOI：
10.1093/hmg/ddn266
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发表时间：
2008-12-01
影响因子：
3.5
通讯作者：
Windle, Jolene J.
中科院分区：
文献类型：
--
作者：
Hiruma, Yuko;Kurihara, Noriyoshi;Windle, Jolene J.
骨的佩吉特病（PDB）是第二常见的骨疾病，其特征在于局灶性骨病变，在高度破骨细胞生成的骨髓微环境中含有大量异常破骨细胞（OCL）和非常活跃的正常成骨细胞。PDB的病因学还不清楚，其发病机制涉及环境和遗传原因。在多达30%的佩吉特患者中发现了SQSTM 1/p62基因突变。为了确定p62突变是否足以诱导PDB，我们产生了携带突变的小鼠，该突变导致残基394处的P至L（脯氨酸至亮氨酸）取代（人p62（P392 L）的鼠等效物，最常见的PDB相关突变）。p62（P394 L）小鼠的骨髓培养物对NF-κ B配体（RANKL）受体激活剂、肿瘤坏死因子α（TNF-α）或1 α，25-（OH）（2）D-3的反应形成了数量增加的OCL，与PDB患者相似。然而，去除基质细胞的纯化的p62（P394 L）OCL前体不再对1 α，25-（OH）（2）D-3高度反应，这表明除了对OCL的直接影响之外，p62（P394 L）突变对骨髓微环境的影响。由于突变基质细胞产生的RANKL增加，纯化的p62（P394 L）基质细胞与野生型（WT）或p62（P394 L）OCL前体的共培养物比含有WT基质细胞的共培养物形成更多的OCL。然而，尽管OCL前体细胞和骨髓基质细胞的破骨细胞生成潜力增强，但p62（P394 L）小鼠的骨组织学正常。这些结果表明，这种PDB相关的p62突变不足以诱导PDB，并表明与p62突变一起作用的其他因素是体内PDB发展所必需的。
Paget's disease of bone (PDB) is the second most common bone disease and is characterized by focal bone lesions which contain large numbers of abnormal osteoclasts (OCLs) and very active normal osteoblasts in a highly osteoclastogenic marrow microenvironment. The etiology of PDB is not well understood and both environmental and genetic causes have been implicated in its pathogenesis. Mutations in the SQSTM1/p62 gene have been identified in up to 30% of Paget's patients. To determine if p62 mutation is sufficient to induce PDB, we generated mice harboring a mutation causing a P-to-L (proline-to-leucine) substitution at residue 394 (the murine equivalent of human p62(P392L), the most common PDB-associated mutation). Bone marrow cultures from p62(P394L) mice formed increased numbers of OCLs in response to receptor activator of NF-kappa B ligand (RANKL), tumor necrosis factor alpha (TNF-alpha) or 1 alpha,25-(OH)(2)D-3, similar to PDB patients. However, purified p62(P394L) OCL precursors depleted of stromal cells were no longer hyper-responsive to 1 alpha,25-(OH)(2)D-3, suggesting effects of the p62(P394L) mutation on the marrow microenvironment in addition to direct effects on OCLs. Co-cultures of purified p62(P394L) stromal cells with either wild-type (WT) or p62(P394L) OCL precursors formed more OCLs than co-cultures containing WT stromal cells due to increased RANKL production by the mutant stromal cells. However, despite the enhanced osteoclastogenic potential of both OCL precursors and marrow stromal cells, the p62(P394L) mice had histologically normal bones. These results indicate that this PDB-associated p62 mutation is not sufficient to induce PDB and suggest that additional factors acting together with p62 mutation are necessary for the development of PDB in vivo.