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Def6调节成骨细胞内源性I型干扰素反应并抑制骨生成。

Def6 regulates endogenous type-I interferon responses in osteoblasts and suppresses osteogenesis.

作者信息

Deng Zhonghao, Ng Courtney, Inoue Kazuki, Chen Ziyu, Xia Yuhan, Hu Xiaoyu, Greenblatt Matthew, Pernis Alessandra, Zhao Baohong

机构信息

Arthritis and Tissue Degeneration Program and David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, United States.

Department of Medicine, Weill Cornell Medical College, New York, United States.

出版信息

Elife. 2020 Dec 29;9:e59659. doi: 10.7554/eLife.59659.

DOI:10.7554/eLife.59659
PMID:33373293
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7771961/
Abstract

Bone remodeling involves a balance between bone resorption and formation. The mechanisms underlying bone remodeling are not well understood. DEF6 is recently identified as a novel loci associated with bone mineral density. However, it is unclear how Def6 impacts bone remodeling. We identify Def6 as a novel osteoblastic regulator that suppresses osteoblastogenesis and bone formation. Def6 deficiency enhances both bone resorption and osteogenesis. The enhanced bone resorption in Def6 mice dominates, leading to osteoporosis. Mechanistically, Def6 inhibits the differentiation of both osteoclasts and osteoblasts via a common mechanism through endogenous type-I IFN-mediated feedback inhibition. RNAseq analysis shows expression of a group of IFN stimulated genes (ISGs) during osteoblastogenesis. Furthermore, we found that Def6 is a key upstream regulator of IFNβ and ISG expression in osteoblasts. Collectively, our results identify a novel immunoregulatory function of Def6 in bone remodeling, and shed insights into the interaction between immune system and bone.

摘要

骨重塑涉及骨吸收与形成之间的平衡。骨重塑的潜在机制尚未完全明确。DEF6最近被鉴定为与骨密度相关的一个新基因座。然而，尚不清楚Def6如何影响骨重塑。我们确定Def6是一种新型成骨调节因子，可抑制成骨细胞生成和骨形成。Def6缺乏会增强骨吸收和成骨作用。Def6基因敲除小鼠中增强的骨吸收占主导地位，导致骨质疏松症。机制上，Def6通过内源性I型干扰素介导的反馈抑制，经由一种共同机制抑制破骨细胞和成骨细胞的分化。RNA测序分析显示在成骨细胞生成过程中有一组干扰素刺激基因（ISG）表达。此外，我们发现Def6是成骨细胞中IFNβ和ISG表达的关键上游调节因子。总体而言，我们的结果确定了Def6在骨重塑中的一种新型免疫调节功能，并为免疫系统与骨之间的相互作用提供了见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b3/7771961/77956899df42/elife-59659-fig6-figsupp2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8b3/7771961/39e5c7f0d60d/elife-59659-fig1.jpg
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