破骨细胞的发育起源、功能维持和基因拯救,Nature

当前位置： X-MOL 学术 › Nature › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

破骨细胞的发育起源、功能维持和基因拯救
Nature ( IF 50.5 ) Pub Date : 2019-04-01 , DOI: 10.1038/s41586-019-1105-7
Christian E Jacome-Galarza ₁ , Gulce I Percin _{2,

3} , James T Muller ₁ , Elvira Mass _{1,

4} , Tomi Lazarov ₁ , Jiri Eitler ₂ , Martina Rauner ₅ , Vijay K Yadav ₆ , Lucile Crozet ₁ , Mathieu Bohm ₁ , Pierre-Louis Loyher ₁ , Gerard Karsenty ₆ , Claudia Waskow _{2,

3,

5} , Frederic Geissmann ₁

Affiliation

破骨细胞是多核巨细胞，可吸收骨骼，确保骨骼和骨髓造血生态位的发育和持续重塑。破骨细胞活性缺陷会导致骨硬化症和骨髓衰竭 1-9，而过度活性会导致骨质流失和骨质疏松症 10。骨硬化症可以通过人类和小鼠的骨髓移植部分治疗 11-18，这与破骨细胞的造血起源一致 13,16,19 和研究表明，它们是通过在 CSF1 和RANK 配体 1,20。然而，破骨细胞的发育起源和寿命，以及在体内确保破骨细胞功能维持的机制在很大程度上仍未被探索。在这里，我们报告定殖胎儿骨化中心的破骨细胞起源于胚胎红细胞 - 骨髓祖细胞21, 22。这些红细胞-骨髓祖细胞衍生的破骨细胞是正常骨骼发育和牙齿萌出所必需的。然而，在新生小鼠中及时输注造血干细胞衍生的单核细胞足以挽救早发性常染色体隐性骨硬化症的骨骼发育。我们还发现，破骨细胞、骨量和骨髓腔的产后维持涉及循环血单核细胞与长寿命破骨细胞合胞体的迭代融合。因此，在没有造血干细胞嵌合的情况下，单核细胞的联体共生或输血导致破骨细胞中的长期基因转移，并且可以挽救由组织蛋白酶 K 缺乏引起的成人发病的骨硬化表型23, 24。总之，我们的研究结果确定了破骨细胞的发育起源以及控制它们在出生后在骨骼中维持的机制。这些数据提出了在骨硬化症中挽救破骨细胞缺乏和调节体内破骨细胞活性的策略。小鼠正常骨骼发育和牙齿萌出所需的多核破骨细胞来源于胚胎红髓细胞祖细胞，并在出生后通过与循环单核细胞融合而维持。

"点击查看英文标题和摘要"

Developmental origin, functional maintenance and genetic rescue of osteoclasts

Osteoclasts are multinucleated giant cells that resorb bone, ensuring development and continuous remodelling of the skeleton and the bone marrow haematopoietic niche. Defective osteoclast activity leads to osteopetrosis and bone marrow failure1–9, whereas excess activity can contribute to bone loss and osteoporosis10. Osteopetrosis can be partially treated by bone marrow transplantation in humans and mice11–18, consistent with a haematopoietic origin of osteoclasts13,16,19 and studies that suggest that they develop by fusion of monocytic precursors derived from haematopoietic stem cells in the presence of CSF1 and RANK ligand1,20. However, the developmental origin and lifespan of osteoclasts, and the mechanisms that ensure maintenance of osteoclast function throughout life in vivo remain largely unexplored. Here we report that osteoclasts that colonize fetal ossification centres originate from embryonic erythro-myeloid progenitors21,22. These erythro-myeloid progenitor-derived osteoclasts are required for normal bone development and tooth eruption. Yet, timely transfusion of haematopoietic-stem-cell-derived monocytic cells in newborn mice is sufficient to rescue bone development in early-onset autosomal recessive osteopetrosis. We also found that the postnatal maintenance of osteoclasts, bone mass and the bone marrow cavity involve iterative fusion of circulating blood monocytic cells with long-lived osteoclast syncytia. As a consequence, parabiosis or transfusion of monocytic cells results in long-term gene transfer in osteoclasts in the absence of haematopoietic-stem-cell chimerism, and can rescue an adult-onset osteopetrotic phenotype caused by cathepsin K deficiency23,24. In sum, our results identify the developmental origin of osteoclasts and a mechanism that controls their maintenance in bones after birth. These data suggest strategies to rescue osteoclast deficiency in osteopetrosis and to modulate osteoclast activity in vivo.Multinucleated osteoclasts required for normal bone development and tooth eruption in the mouse originate from embryonic erythro-myeloid progenitors and are maintained after birth by fusion with circulating monocytes.

更新日期：2019-04-01

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南