RANKL 反向信号转导耦联骨吸收与形成。
Coupling of bone resorption and formation by RANKL reverse signalling.
机构信息
Department of Pharmacy, the University of Tokyo Hospital, Faculty of Medicine, the University of Tokyo, Tokyo, Japan.
Department of Basic Oral Health Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
出版信息
Nature. 2018 Sep;561(7722):195-200. doi: 10.1038/s41586-018-0482-7. Epub 2018 Sep 5.
Receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) binds RANK on the surface of osteoclast precursors to trigger osteoclastogenesis. Recent studies have indicated that osteocytic RANKL has an important role in osteoclastogenesis during bone remodelling; however, the role of osteoblastic RANKL remains unclear. Here we show that vesicular RANK, which is secreted from the maturing osteoclasts, binds osteoblastic RANKL and promotes bone formation by triggering RANKL reverse signalling, which activates Runt-related transcription factor 2 (Runx2). The proline-rich motif in the RANKL cytoplasmic tail is required for reverse signalling, and a RANKL(Pro29Ala) point mutation reduces activation of the reverse signalling pathway. The coupling of bone resorption and formation is disrupted in RANKL(Pro29Ala) mutant mice, indicating that osteoblastic RANKL functions as a coupling signal acceptor that recognizes vesicular RANK. RANKL reverse signalling is therefore a potential pharmacological target for avoiding the reduced bone formation associated with inhibition of osteoclastogenesis.
核因子-κB 受体激活剂配体（RANKL）与破骨细胞前体细胞表面的 RANK 结合，引发破骨细胞生成。最近的研究表明，在骨重塑过程中，骨细胞 RANKL 在破骨细胞生成中具有重要作用；然而，成骨细胞 RANKL 的作用尚不清楚。本文表明，从成熟破骨细胞分泌的囊泡 RANK 与成骨细胞 RANKL 结合，并通过触发 RANKL 反向信号转导来促进骨形成，该信号转导激活 Runt 相关转录因子 2（Runx2）。RANKL 细胞质尾部的富含脯氨酸基序是反向信号转导所必需的，而 RANKL（Pro29Ala）点突变会降低反向信号通路的激活。RANKL（Pro29Ala）突变小鼠中骨吸收和形成的偶联被破坏，表明成骨细胞 RANKL 作为识别囊泡 RANK 的偶联信号受体发挥作用。因此，RANKL 反向信号转导是一种潜在的药理学靶点，可以避免与抑制破骨细胞生成相关的骨形成减少。
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