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Abstract：
UNASSIGNED: Recently, the osteogenic potential of Adiponectin-labeled adipogenic lineage progenitors (Adipoq-lineage progenitors) in bone marrow has been observed to support bone maintenance and repair. However, little is known about the function of Schnurri-3 (SHN3, also known as HIVEP3) in other mesenchymal lineage cells, apart from its negative regulation of bone formation on osteoblasts.
UNASSIGNED: In this study, we used single-cell RNA sequencing (scRNA-seq) profiling to demonstrate that Adipoq-lineage progenitors express higher levels of Shn3 compared to other mesenchymal cell populations in mice and humans. To investigate the role of SHN3 in Adipoq-lineage progenitors, we generated a murine model specifically harboring a Shn3-deficient allele in Adipoq-expressing cells. Information of mice body weight was collected weekly to generate body weight curve. Bone phenotype was analyzed using micro-CT and histomorphometric studies. To eliminate the role of peripheral adipose tissue on bone, we collected adipose wet weight, performed intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests, and conducted a fat-transplantation study. Osteoblast and osteoclast functions were assessed through toluidine blue staining and TRAP staining, respectively. We further investigated the effect of Shn3 depletion on the differentiation of Adipoq-lineage progenitors through immunostaining and in vitro differentiation assays. Finally, we evaluated whether Shn3 deficiency in Adipoq-lineage progenitors affects the fracture healing process by generating bi-cortical femoral fracture models.
UNASSIGNED: Depletion of Shn3 in Adipoq-lineage progenitors resulted in a significant increase in trabecular bone mass and bone formation in vivo, without disrupting whole-body energy metabolism and skeletal development. Consistent with these findings, both cell-lineage tracing and functional assays revealed that Shn3 ablation effectively shifted the cell fate of Adipoq-lineage progenitors towards an osteogenic phenotype in the bone marrow. Furthermore, in vivo studies demonstrated that the lack of Shn3 in Adipoq-lineage progenitors also enhanced bone fracture healing under pathological conditions.
UNASSIGNED: Overall, our findings provide a novel strategy for targeting the osteoanabolic potential of bone marrow Adipoq-lineage progenitors as a potential treatment for bone loss-related disorders.
UNASSIGNED: We have identified a novel gene target that directs the cell fate of a previously identified non-osteogenic cell population under physiological conditions. This study not only expands the therapeutic value of Shn3 ablation in treating osteoporotic or traumatic bone diseases but also provides new insights into the contribution of bone marrow Adipoq-lineage progenitors to osteogenesis. Thus, this article further supports Shn3 silencing as a valuable approach to treat osteopenia and accelerate fracture healing (see graphical abstract).
UNASSIGNED: In this study, we used single-cell RNA sequencing (scRNA-seq) profiling to demonstrate that Adipoq-lineage progenitors express higher levels of Shn3 compared to other mesenchymal cell populations in mice and humans. To investigate the role of SHN3 in Adipoq-lineage progenitors, we generated a murine model specifically harboring a Shn3-deficient allele in Adipoq-expressing cells. Information of mice body weight was collected weekly to generate body weight curve. Bone phenotype was analyzed using micro-CT and histomorphometric studies. To eliminate the role of peripheral adipose tissue on bone, we collected adipose wet weight, performed intraperitoneal glucose tolerance tests and intraperitoneal insulin tolerance tests, and conducted a fat-transplantation study. Osteoblast and osteoclast functions were assessed through toluidine blue staining and TRAP staining, respectively. We further investigated the effect of Shn3 depletion on the differentiation of Adipoq-lineage progenitors through immunostaining and in vitro differentiation assays. Finally, we evaluated whether Shn3 deficiency in Adipoq-lineage progenitors affects the fracture healing process by generating bi-cortical femoral fracture models.
UNASSIGNED: Depletion of Shn3 in Adipoq-lineage progenitors resulted in a significant increase in trabecular bone mass and bone formation in vivo, without disrupting whole-body energy metabolism and skeletal development. Consistent with these findings, both cell-lineage tracing and functional assays revealed that Shn3 ablation effectively shifted the cell fate of Adipoq-lineage progenitors towards an osteogenic phenotype in the bone marrow. Furthermore, in vivo studies demonstrated that the lack of Shn3 in Adipoq-lineage progenitors also enhanced bone fracture healing under pathological conditions.
UNASSIGNED: Overall, our findings provide a novel strategy for targeting the osteoanabolic potential of bone marrow Adipoq-lineage progenitors as a potential treatment for bone loss-related disorders.
UNASSIGNED: We have identified a novel gene target that directs the cell fate of a previously identified non-osteogenic cell population under physiological conditions. This study not only expands the therapeutic value of Shn3 ablation in treating osteoporotic or traumatic bone diseases but also provides new insights into the contribution of bone marrow Adipoq-lineage progenitors to osteogenesis. Thus, this article further supports Shn3 silencing as a valuable approach to treat osteopenia and accelerate fracture healing (see graphical abstract).
摘要：
■最近，已经观察到骨髓中脂联素标记的脂肪谱系祖细胞(Adipoq谱系祖细胞)的成骨潜力支持骨维持和修复。然而,关于Schnurri-3（SHN3，也称为HIVEP3）在其他间质谱系细胞中的功能知之甚少，除了它对成骨细胞的骨形成的负调节。
■在这项研究中，我们使用单细胞RNA测序(scRNA-seq)分析证明,与小鼠和人类的其他间充质细胞群体相比,Adipoq谱系祖细胞表达更高水平的Shn3.为了研究SHN3在Adipoq谱系祖细胞中的作用，我们建立了一个小鼠模型，该模型在表达Adipoq的细胞中特异性地含有一个Shn3缺陷型等位基因。每周收集小鼠体重的信息以产生体重曲线。使用显微CT和组织形态学研究分析骨表型。为了消除周围脂肪组织对骨骼的作用，我们收集了脂肪湿重，进行腹膜内葡萄糖耐量试验和腹膜内胰岛素耐量试验,并进行了脂肪移植研究。通过甲苯胺蓝染色和TRAP染色评估成骨细胞和破骨细胞功能，分别。我们通过免疫染色和体外分化测定进一步研究了Shn3耗竭对Adipoq谱系祖细胞分化的影响。最后,我们通过建立股骨双皮质骨折模型,评估了Adipoq谱系祖细胞中的Shn3缺乏是否会影响骨折愈合过程.
■在Adipoq谱系祖细胞中消耗Shn3导致体内骨小梁质量和骨形成显着增加，不破坏全身能量代谢和骨骼发育。与这些发现一致，细胞谱系追踪和功能测定均显示,Shn3消融有效地将Adipoq谱系祖细胞的细胞命运转变为骨髓中的成骨表型.此外，体内研究表明，Adipoq谱系祖细胞中Shn3的缺乏也增强了病理条件下的骨折愈合。
■总的来说，我们的研究结果为靶向骨髓Adipoq谱系祖细胞的骨合成代谢潜能提供了一种新的策略,作为骨丢失相关疾病的潜在治疗方法.
■我们已经鉴定了一种新的基因靶标，该靶标指导先前鉴定的非成骨细胞群体在生理条件下的细胞命运。这项研究不仅扩展了Shn3消融在治疗骨质疏松或创伤性骨骼疾病中的治疗价值，而且还提供了有关骨髓Adipoq谱系祖细胞对成骨作用的新见解。因此，本文进一步支持将Shn3沉默作为治疗骨质减少和加速骨折愈合的有价值的方法(见图形摘要).
■在这项研究中，我们使用单细胞RNA测序(scRNA-seq)分析证明,与小鼠和人类的其他间充质细胞群体相比,Adipoq谱系祖细胞表达更高水平的Shn3.为了研究SHN3在Adipoq谱系祖细胞中的作用，我们建立了一个小鼠模型，该模型在表达Adipoq的细胞中特异性地含有一个Shn3缺陷型等位基因。每周收集小鼠体重的信息以产生体重曲线。使用显微CT和组织形态学研究分析骨表型。为了消除周围脂肪组织对骨骼的作用，我们收集了脂肪湿重，进行腹膜内葡萄糖耐量试验和腹膜内胰岛素耐量试验,并进行了脂肪移植研究。通过甲苯胺蓝染色和TRAP染色评估成骨细胞和破骨细胞功能，分别。我们通过免疫染色和体外分化测定进一步研究了Shn3耗竭对Adipoq谱系祖细胞分化的影响。最后,我们通过建立股骨双皮质骨折模型,评估了Adipoq谱系祖细胞中的Shn3缺乏是否会影响骨折愈合过程.
■在Adipoq谱系祖细胞中消耗Shn3导致体内骨小梁质量和骨形成显着增加，不破坏全身能量代谢和骨骼发育。与这些发现一致，细胞谱系追踪和功能测定均显示,Shn3消融有效地将Adipoq谱系祖细胞的细胞命运转变为骨髓中的成骨表型.此外，体内研究表明，Adipoq谱系祖细胞中Shn3的缺乏也增强了病理条件下的骨折愈合。
■总的来说，我们的研究结果为靶向骨髓Adipoq谱系祖细胞的骨合成代谢潜能提供了一种新的策略,作为骨丢失相关疾病的潜在治疗方法.
■我们已经鉴定了一种新的基因靶标，该靶标指导先前鉴定的非成骨细胞群体在生理条件下的细胞命运。这项研究不仅扩展了Shn3消融在治疗骨质疏松或创伤性骨骼疾病中的治疗价值，而且还提供了有关骨髓Adipoq谱系祖细胞对成骨作用的新见解。因此，本文进一步支持将Shn3沉默作为治疗骨质减少和加速骨折愈合的有价值的方法(见图形摘要).
