Sexually Dimorphic Increases in Bone Mass Following Tissue-specific Overexpression of Runx1 in Osteoclast Precursors
Sexually Dimorphic Increases in Bone Mass Following Tissue-specific Overexpression of Runx1 in Osteoclast Precursors
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DOI：
10.1210/endocr/bqac113
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发表时间：
2022-09-01
期刊：
影响因子：
4.8
通讯作者：
Drissi, Hicham
中科院分区：
文献类型：
--
作者：
Diaz-Hernandez, Martha Elena;Kinter, Christopher W.;Drissi, Hicham
许多代谢性骨疾病的发生是由于过度的破骨细胞性骨吸收，这促使人们努力寻找新的分子靶点来抑制这些骨吸收细胞的形成或活性。越来越多的证据表明，转录因子RUNX1是破骨细胞形成的转录抑制因子。先前使用条件性基因敲除方法的研究表明，破骨细胞前体中的RUNX1作为破骨细胞生成的抑制因子；然而，RUNX1上调对破骨细胞形成的影响尚不清楚。在这项研究中，我们通过将新的RUNX1功能获得小鼠(rosa26-LSL-RUNX1)与LysM-Cre转基因小鼠杂交，研究了RUNX1在破骨前细胞中条件性过表达对骨骼的影响。我们观察到一种性别依赖的效应，即在雌性小鼠中过表达RUNX1增加了骨小梁微结构指数，并改善了扭转生物力学性能。这些作用可能是通过延迟破骨细胞形成和减少骨吸收来实现的。破骨细胞形成过程中的转录学分析显示，在RUNX1过表达的细胞中有一个独特的转录图谱，与氧化还原信号、细胞凋亡、破骨细胞分化和骨重建相关的基因丰富。这些数据进一步证实了RUNX1的抗破骨细胞活性，并为可能介导这些作用的分子靶点提供了新的见解。
Many metabolic bone diseases arise as a result excessive osteoclastic bone resorption, which has motivated efforts to identify new molecular targets that can inhibit the formation or activity of these bone-resorbing cells. Mounting evidence indicates that the transcription factor Runx1 acts as a transcriptional repressor of osteoclast formation. Prior studies using a conditional knockout approach suggested that Runx1 in osteoclast precursors acts as an inhibitor of osteoclastogenesis; however, the effects of upregulation of Runx1 on osteoclast formation remain unknown. In this study, we investigated the skeletal effects of conditional overexpression of Runx1 in preosteoclasts by crossing novel Runx1 gain-of-function mice (Rosa26-LSL-Runx1) with LysM-Cre transgenic mice. We observed a sex-dependent effect whereby overexpression of Runx1 in female mice increased trabecular bone microarchitectural indices and improved torsion biomechanical properties. These effects were likely mediated by delayed osteoclastogenesis and decreased bone resorption. Transcriptomics analyses during osteoclastogenesis revealed a distinct transcriptomic profile in the Runx1-overexpressing cells, with enrichment of genes related to redox signaling, apoptosis, osteoclast differentiation, and bone remodeling. These data further confirm the antiosteoclastogenic activities of Runx1 and provide new insight into the molecular targets that may mediate these effects.