ELMO1 signaling is a promoter of osteoclast function and bone loss.
ELMO1 signaling is a promoter of osteoclast function and bone loss.
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ELMO1信号传导是破骨细胞功能和骨质流失的启动子。
DOI：
10.1038/s41467-021-25239-6
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发表时间：
2021-08-17
影响因子：
16.6
通讯作者：
Ravichandran KS
中科院分区：
文献类型：
--
作者：
Arandjelovic S;Perry JSA;Zhou M;Ceroi A;Smirnov I;Walk SF;Shankman LS;Cambré I;Onengut-Gumuscu S;Elewaut D;Conrads TP;Ravichandran KS
骨质疏松症影响全世界数百万人，通常是由破骨细胞引起的骨丢失引起的。在这里，我们确定细胞质蛋白ELMO 1作为一个重要的“信号节点”在破骨细胞。我们注意到ELMO 1单核苷酸多态性与人类骨异常相关，并且小鼠ELMO 1缺失减少了四种体内模型的骨丢失：骨保护素缺乏症，卵巢切除术和两种类型的炎性关节炎。我们的转录组学分析加上CRISPR/Cas9基因缺失鉴定了Elmo 1相关的破骨细胞功能调节因子，包括组织蛋白酶G和髓过氧化物酶。此外，我们通过蛋白质组学定义破骨细胞中的“ELMO 1相互作用组”，并揭示骨降解所需的蛋白质。ELMO 1还有助于骨样表面上的破骨细胞密封区和破骨细胞特异性蛋白酶的分布。最后，基于3D结构的ELMO 1抑制肽减少野生型破骨细胞的骨吸收。总的来说，我们确定ELMO 1作为一个信号枢纽，调节破骨细胞功能和骨丢失，与骨质疏松症和关节炎。骨质疏松症和骨折影响全世界数百万患者，通常是由于骨吸收增加。在这里，作者确定细胞质蛋白ELMO 1作为一个重要的“信号节点”，促进破骨细胞的骨吸收功能。
Osteoporosis affects millions worldwide and is often caused by osteoclast induced bone loss. Here, we identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ in osteoclasts. We note that ELMO1 SNPs associate with bone abnormalities in humans, and that ELMO1 deletion in mice reduces bone loss in four in vivo models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. Our transcriptomic analyses coupled with CRISPR/Cas9 genetic deletion identify Elmo1 associated regulators of osteoclast function, including cathepsin G and myeloperoxidase. Further, we define the ‘ELMO1 interactome’ in osteoclasts via proteomics and reveal proteins required for bone degradation. ELMO1 also contributes to osteoclast sealing zone on bone-like surfaces and distribution of osteoclast-specific proteases. Finally, a 3D structure-based ELMO1 inhibitory peptide reduces bone resorption in wild type osteoclasts. Collectively, we identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to osteoporosis and arthritis. Osteoporosis and bone fractures affect millions of patients worldwide and are often due to increased bone resorption. Here the authors identify the cytoplasmic protein ELMO1 as an important ‘signaling node’ promoting the bone resorption function of osteoclasts.