A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss
A TNF receptor loop peptide mimic blocks RANK ligand-induced signaling, bone resorption, and bone loss
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DOI：
10.1172/jci22513
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发表时间：
2006-06-01
影响因子：
15.9
通讯作者：
Baron, Roland
中科院分区：
文献类型：
--
作者：
Aoki, Kazuhiro;Saito, Hiroaki;Baron, Roland
激活 NF-κ B (RANK) 和 TNF 受体 (TNFR) 受体激活剂可促进破骨细胞分化。 TNFR 上的一个关键配体接触位点在 RANK 中部分保守。表面等离振子共振研究表明，一种肽 (WP9QY) 模拟了 TNFR 接触位点，并抑制 TNF-α 诱导的与 RANK 配体 (RANKL) 结合的活性。改变预计在相互作用中发挥重要作用的单个残基会显着减少结合。 WP9QY（而非改变的对照肽）抑制 RAW 264.7 细胞中 RANKL 诱导的 RANK 依赖性信号传导激活，但对 M-CSF 诱导的一些相同信号传导事件的激活没有影响。即使 TNFR 不存在或被阻断，WP9QY（而非对照肽）也能阻止 RANKL 诱导的骨吸收和破骨细胞生成。在体内，RANKL 和 TNF-α 均促进破骨细胞生成、破骨细胞活性和骨质流失，而 WP9QY 可以阻止卵巢切除或低膳食钙诱导的小鼠破骨细胞生成和骨质流失增加，在后一种情况下，野生型和 TNFR 双敲除小鼠均如此。这些结果表明，模拟 TNFR 配体接触位点的肽通过干扰 RANKL 和 TNF 的破骨细胞募集和激活来阻断骨吸收。
Activating receptor activator of NF-kappa B (RANK) and TNF receptor (TNFR) promote osteoclast differentiation. A critical ligand contact site on the TNFR is partly conserved in RANK. Surface plasmon resonance studies showed that a peptide (WP9QY) that mimics this TNFR contact site and inhibits TNF-alpha-induced activity bound to RANK ligand (RANKL). Changing a single residue predicted to play an important role in the interaction reduced the binding significantly. WP9QY, but not the altered control peptide, inhibited the RANKL-induced activation of RANK-dependent signaling in RAW 264.7 cells but had no effect on M-CSF-induced activation of some of the same signaling events. WP9QY but not the control peptide also prevented RANKL-induced bone resorption and osteoclastogenesis, even when TNFRs were absent or blocked. In vivo, where both RANKL and TNF-alpha promote osteoclastogenesis, osteoclast activity, and bone loss, WP9QY prevented the increased osteoclastogenesis and bone loss induced in mice by ovariectomy or low dietary calcium, in the latter case in both wild-type and TNFR double-knockout mice. These results suggest that a peptide that mimics a TNFR ligand contact site blocks bone resorption by interfering with recruitment and activation of osteoclasts by both RANKL and TNF.