Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice
Transient receptor potential vanilloid 1 and 4 double knockout leads to increased bone mass in mice
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DOI：
10.1016/j.bonr.2020.100268
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发表时间：
2020-06-01
期刊：
影响因子：
2.5
通讯作者：
Sakai, Akinori
中科院分区：
文献类型：
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作者：
Nishimura, Haruki;Kawasaki, Makoto;Sakai, Akinori
钙平衡在骨稳态中是重要的。瞬时受体电位香草酸（TRPV）通道是一种非选择性的钙离子通道，可被多种生理和药理刺激激活。特别是TRPV1和TRPV4在骨细胞的细胞内Ca2+信号传导和细胞外钙稳态中具有重要作用。TRPV1和TRPV4分别介导破骨细胞和成骨细胞的分化，这些通道中任何一个的缺乏都会导致骨量增加。然而，在缺乏TRPV1和TRPV4的情况下，骨量是否增加仍然未知。在这项研究中，我们使用TRPV1和TRPV4双敲除（DKO）小鼠，以评估其体内骨量，破骨细胞和成骨细胞分化在体外。我们的结果显示，DKO小鼠和野生型（WT）小鼠的体重和股骨长度没有显着差异。然而，双能X射线吸收、显微计算机断层扫描和骨组织形态计量学的结果清楚地表明，DKO小鼠的骨量高于WT小鼠。此外，DKO小鼠的多核破骨细胞较少，骨吸收较低。此外，使用来自小鼠股骨和胫骨的冲洗骨髓进行细胞培养的结果显示，破骨细胞分化受到抑制，而DKO小鼠中的成骨细胞分化得到促进。总之，我们的结果表明，DKO小鼠骨量的增加不仅是通过抑制破骨细胞分化和活性来诱导的，而且是通过增强成骨细胞分化和活性来诱导的。我们的研究结果表明，无论是单一的TRPVs的缺陷和并发TRPVs的缺陷导致骨量增加。此外，我们的数据显示，DKO小鼠和单KO小鼠在体外有不同的破骨细胞和成骨细胞分化方法，因此，重要的是要对TRPV进行进一步的研究，以探讨不仅是单个TRPV，而且是TRPV的组合。
Calcium balance is important in bone homeostasis. The transient receptor potential vanilloid (TRPV) channel is a nonselective cation channel permeable to calcium and is activated by various physiological and pharmacological stimuli. TRPV1 and TRPV4, in particular, have important roles in intracellular Ca2+ signaling and extracellular calcium homeostasis in bone cells. TRPV1 and TRPV4 separately mediate osteoclast and osteoblast differentiation, and deficiency in any of these channels leads to increased bone mass. However, it remains unknown whether bone mass increases in the absence of both TRPV1 and TRPV4. In this study, we used TRPV1 and TRPV4 double knockout (DKO) mice to evaluate their bone mass in vivo, and osteoclast and osteoblast differentiation in vitro. Our results showed that DKO mice and wild type (WT) mice had no significant difference in body weight and femur length. However, the results of dual-energy X-ray absorption, microcomputed tomography, and bone histomorphometry clearly showed that DKO mice had higher bone mass than WT mice. Furthermore, DKO mice had less multinucleated osteoclasts and had lower bone resorption. In addition, the results of cell culture using flushed bone marrow from mouse femurs and tibias showed that osteoclast differentiation was suppressed, whereas osteoblast differentiation was promoted in DKO mice. In conclusion, our results suggest that the increase in bone mass in DKO mice was induced not only by the suppression of osteoclast differentiation and activity but also by the augmentation of osteoblast differentiation and activity. Our findings reveal that both the single deficiency of TRPVs and the concurrent deficiency of TRPVs result in an increase in bone mass. Furthermore, our data showed that DKO mice and single KO mice had varying approaches to osteoclast and osteoblast differentiation in vitro, and therefore, it is important to conduct further studies on TRPVs regarding the increase in bone mass to explore not only individual but also a combination of TRPVs.