成骨细胞中polycystin-1和Wwtr1之间的遗传相互作用确定了一种新的调节小鼠骨形成的机械传感机制。

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Zhousheng Xiao, Li Cao, Micholas Dean Smith, Hanxuan Li, Wei Li, Jeremy C Smith, Leigh Darryl Quarles
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引用次数: 0

摘要

在骨微环境中传递物理力以调节骨量的分子机制尚不清楚。在这里,我们使用小鼠遗传学、机械负荷和药理学方法来测试多囊蛋白-1和Wwtr1在成骨细胞中具有相互依赖的机械传感功能的可能性。我们创建并比较了对照Pkd1flox/+的骨骼表型;Wwtr1flox/+、Pkd1Oc cKO、Wwtr1Oc cKO和Pkd1/Wwtr1Oc-cKO小鼠,以研究遗传相互作用。与体内骨中微囊藻毒素和Wwtr1之间的相互作用一致,Pkd1/Wwtr1Oc-cKO小鼠比Wwtr1Oc-cKO或Pkd1Oc-cKO小鼠表现出更大的BMD和骨膜MAR降低。Micro-CT 3D图像分析表明,与Pkd1Oc cKO或Wwtr1Oc cKO小鼠相比,Pkd1/Wwtr1Oc-cKO小鼠的骨量减少是由于小梁骨体积和皮质骨厚度的损失更大。与Pkd1Oc cKO或Wwtr1Oc cKO小鼠相比,Pkd1/Wwtr1Oc-cKO小鼠在骨中的机械感应和成骨基因表达谱也显示出加性降低。此外,我们发现,与对照小鼠相比,Pkd1/Wwtr1Oc-cKO小鼠在体内对胫骨机械负荷的反应受损,负荷诱导的机械感应基因表达减弱。最后,与载体对照相比,用激活polycystin复合物的小分子机械模拟物MS2处理的对照小鼠导致股骨BMD和骨膜MAR显著增加。相反,Pkd1/Wwtr1Oc-cKO小鼠对MS2的合成代谢作用具有抗性。这些发现表明PC1和Wwtr1形成合成代谢机械转导信号复合体,介导机械负荷反应,并作为治疗骨质疏松症的潜在新治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.

Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.

Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.

Genetic interactions between polycystin-1 and Wwtr1 in osteoblasts define a novel mechanosensing mechanism regulating bone formation in mice.

Molecular mechanisms transducing physical forces in the bone microenvironment to regulate bone mass are poorly understood. Here, we used mouse genetics, mechanical loading, and pharmacological approaches to test the possibility that polycystin-1 and Wwtr1 have interdependent mechanosensing functions in osteoblasts. We created and compared the skeletal phenotypes of control Pkd1flox/+;Wwtr1flox/+, Pkd1Oc-cKO, Wwtr1Oc-cKO, and Pkd1/Wwtr1Oc-cKO mice to investigate genetic interactions. Consistent with an interaction between polycystins and Wwtr1 in bone in vivo, Pkd1/Wwtr1Oc-cKO mice exhibited greater reductions of BMD and periosteal MAR than either Wwtr1Oc-cKO or Pkd1Oc-cKO mice. Micro-CT 3D image analysis indicated that the reduction in bone mass was due to greater loss in both trabecular bone volume and cortical bone thickness in Pkd1/Wwtr1Oc-cKO mice compared to either Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Pkd1/Wwtr1Oc-cKO mice also displayed additive reductions in mechanosensing and osteogenic gene expression profiles in bone compared to Pkd1Oc-cKO or Wwtr1Oc-cKO mice. Moreover, we found that Pkd1/Wwtr1Oc-cKO mice exhibited impaired responses to tibia mechanical loading in vivo and attenuation of load-induced mechanosensing gene expression compared to control mice. Finally, control mice treated with a small molecule mechanomimetic, MS2 that activates the polycystin complex resulted in marked increases in femoral BMD and periosteal MAR compared to vehicle control. In contrast, Pkd1/Wwtr1Oc-cKO mice were resistant to the anabolic effects of MS2. These findings suggest that PC1 and Wwtr1 form an anabolic mechanotransduction signaling complex that mediates mechanical loading responses and serves as a potential novel therapeutic target for treating osteoporosis.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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