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Osteopetrosis in mice lacking haematopoietic transcription factor PU.1

机译：缺乏造血转录因子PU.1的小鼠的骨质疏松

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摘要

Osteoclasts are multinucleated cells and the principal resorptive cells of bone. Although osteoclasts are of myeloid origin, the role of haematopoietic transcription factors in osteoclastogenesis has not been explored. Here we show that messenger RNA for the myeloid- and B-cell-specific transcription factor PU.1 progressively increases as marrow macrophages assume the osteoclast phenotype in vitro. The association between PU.1 and osteoclast differentiation was confirmed by demonstrating that PU.1 expression increased with the induction of osteoclastogenesis by either 1,25-dihydroxyvitamin D3 or dexamethasone. Consistent with the participation of PU.1 in osteoclastogenesis, we found that the development of both osteoclasts and macrophages is arrested in PU.1-deficient mice. Reflecting the absence of osteoclasts, PU.1-/- mice exhibit the classic hallmarks of osteopetrosis, a family of sclerotic bone diseases. These animals were rescued by marrow transplantation, with complete restoration of osteoclast and macrophage differentiation, verifying that the PU.1 lesion is intrinsic to haematopoietic cells. The absence of both osteoclasts and macrophages in PU.1-mutant animals suggests that the transcription factor regulates the initial stages of myeloid differentiation, and that its absence represents the earliest developmental osteopetrotic mutant yet described.
机译：破骨细胞是骨骼的多核细胞和主要的吸收性细胞。尽管破骨细胞起源于骨髓，但尚未探讨造血转录因子在破骨细胞形成中的作用。在这里，我们显示髓样和B细胞特异性转录因子PU.1的信使RNA随着骨髓巨噬细胞在体外呈现破骨细胞表型而逐渐增加。 PU.1与破骨细胞分化之间的关联通过证实1,25-二羟基维生素D3或地塞米松诱导破骨细胞生成增加了PU.1表达。与参与破骨细胞形成的PU.1一致，我们发现破骨细胞和巨噬细胞的发育在PU.1缺陷小鼠中被阻止。反映出没有破骨细胞，PU.1-/-小鼠表现出骨硬化症（一种硬化性骨病家族）的经典标志。通过骨髓移植拯救了这些动物，破骨细胞和巨噬细胞的分化得以完全恢复，从而证实了PU.1病变是造血细胞所固有的。 PU.1突变动物中既没有破骨细胞又没有巨噬细胞，这表明转录因子调节了骨髓分化的初始阶段，并且它的缺失代表了迄今描述的最早的发育性骨石突变体。

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