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.
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DOI：
10.1038/s41413-023-00295-4
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发表时间：
2023-10-26
期刊：
影响因子：
12.7
通讯作者：
Quarles, Leigh Darryl
中科院分区：
文献类型：
--
作者：
Xiao, Zhousheng;Cao, Li;Smith, Micholas Dean;Li, Hanxuan;Li, Wei;Smith, Jeremy C.;Quarles, Leigh Darryl
在骨微环境中转导物理力以调节骨量的分子机制知之甚少。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的可能性，多囊蛋白-1和Wwtr 1在成骨细胞中具有相互依赖的机械传感功能。我们创建并比较了对照Pkd 1flox/+、Wwtr 1flox/+、Pkd 1 Oc-cKO、Wwtr 1 Oc-cKO和Pkd 1/Wwtr 1 Oc-cKO小鼠的骨骼表型，以研究遗传相互作用。与体内骨中多囊蛋白和Wwtr 1之间的相互作用一致，Pkd 1/Wwtr 1 Oc-cKO小鼠的BMD和骨膜MAR降低程度大于Wwtr 1 Oc-cKO或Pkd 1 Oc-cKO小鼠。Micro-CT 3D图像分析表明，骨量减少是由于与Pkd 1 Oc-cKO或Wwtr 1 Oc-cKO小鼠相比，Pkd 1/Wwtr 1 Oc-cKO小鼠的松质骨体积和皮质骨厚度损失更大。与Pkd 1 Oc-cKO或Wwtr 1 Oc-cKO小鼠相比，Pkd 1/Wwtr 1 Oc-cKO小鼠在骨中的机械传感和成骨基因表达谱中也显示出附加性降低。此外，我们发现，Pkd 1/Wwtr 1 Oc-cKO小鼠表现出受损的反应，胫骨在体内的机械负荷和衰减负载诱导的mechanosensing基因的表达相比，对照组小鼠。最后，与载体对照相比，用激活多囊蛋白复合物的小分子机械模拟物MS 2处理的对照小鼠导致股骨BMD和骨膜MAR显著增加。相比之下，Pkd 1/Wwtr 1 Oc-cKO小鼠对MS 2的合成代谢作用具有抗性。这些研究结果表明，PC 1和Wwtr 1形成一个合成代谢机械转导信号复合物，介导机械负荷反应，并作为一个潜在的新的治疗骨质疏松症的治疗靶点。
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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影响因子：
19.6
作者：
Gitomer B;Pereira R;Salusky IB;Stoneback JW;Isakova T;Cai X;Dalrymple LS;Ofsthun N;You Z;Malluche HH;Maddux F;George D;Torres V;Chapman A;Steinman TI;Wolf M;Chonchol M
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影响因子：
2.5
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通讯作者：
Chebib, Fouad T.
影响因子：
3.5
作者：
Merrick, David;Mistry, Kavita;Caplan, Michael J.
通讯作者：
Caplan, Michael J.
DOI：
10.1097/01.asn.0000144204.01352.86
发表时间：
2004-12-01
影响因子：
13.6
作者：
Piontek, KB;Huso, DL;Germino, GG
通讯作者：
Germino, GG
DOI：
10.1016/j.bbrc.2015.11.006
发表时间：
2015-12-04
影响因子：
3.1
作者：
Chen, Zhe;Luo, Qing;Song, Guanbin
通讯作者：
Song, Guanbin