Coupling of bone resorption and formation by RANKL reverse signalling

被引：562

作者：

Ikebuchi, Yuki ^{[1
]}

Aoki, Shigeki ^{[1
]}

Honma, Masashi ^{[1
]}

Hayashi, Madoka ^{[1
]}

Sugamori, Yasutaka ^{[2
]}

Khan, Masud ^{[2
]}

Kariya, Yoshiaki ^{[1
]}

Kato, Genki ^{[3
]}

Tabata, Yasuhiko ^{[4
]}

Penninger, Josef M. ^{[5
]}

Udagawa, Nobuyuki ^{[6
]}

Aoki, Kazuhiro ^{[2
]}

Suzuki, Hiroshi ^{[1
]}

机构：

[1] Univ Tokyo, Univ Tokyo Hosp, Dept Pharm, Fac Med, Tokyo, Japan

[2] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Basic Oral Hlth Engn, Tokyo, Japan

[3] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Biomatrix Pharmacol, Tokyo, Japan

[4] Kyoto Univ, Inst Frontier Life & Med Sci, Dept Regenerat Sci & Engn, Lab Biomat, Kyoto, Japan

[5] Austrian Acad Sci, Vienna Bioctr, Inst Mol Biotechnol, Vienna, Austria

[6] Matsumoto Dent Univ, Dept Biochem, Shiojiri, Japan

来源：

NATURE | 2018年 / 561卷 / 7722期

关键词：

MESENCHYMAL STEM-CELLS; OSTEOBLAST DIFFERENTIATION; OSTEOCLASTOGENESIS; GROWTH; MICE; PROLIFERATION; SUPPRESSION; EXPRESSION; VESICLES;

D O I：

10.1038/s41586-018-0482-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：195 / +

页数：19

共 34 条

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Suppression of NF-κB Increases Bone Formation and Ameliorates Osteopenia in Ovariectomized Mice [J].