The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption
The epithelial Ca2+ channel TRPV5 is essential for proper osteoclastic bone resorption
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DOI：
10.1073/pnas.0505789102
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发表时间：
2005-11-29
影响因子：
11.1
通讯作者：
van Leeuwen, JPTM
中科院分区：
文献类型：
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作者：
van der Eerden, BCJ;Hoenderop, JGJ;van Leeuwen, JPTM
骨重塑涉及骨吸收和骨形成的相互作用，并被精确控制以维持骨量。这两个过程都需要跨细胞Ca2+运输，但参与的分子机制在很大程度上仍然难以捉摸。上皮Ca2+通道TRIPV5是最具Ca2+选择性的瞬时受体电位（TRP）通道之一。本研究探讨了TRPV5在骨中的功能作用。TRPV5 mRNA在人和鼠骨样本和破骨细胞中表达，与其他参与细胞间Ca2+运输的基因一起表达，包括calbinin - d - 9k和calbinin - d - 28k、Na+/Ca2+交换器1和质膜Ca2+- atp酶1b。免疫染色证实TRPV5在小鼠破骨细胞中的表达，主要定位于皱褶边缘膜。而TRPV5在成骨细胞中缺失。对TRPV5敲除（TRPV5(-/-)）小鼠股骨切片的分析显示，破骨细胞数量和破骨细胞面积增加，而尿骨吸收标志物脱氧吡啶啉与WT （TRPV5(+/+)）小鼠相比减少。在体外骨髓培养系统中，与TRPV5（+/+）小鼠相比，TRPV5（-/-）小鼠的破骨细胞数量和每个破骨细胞的细胞核数量显著增加。然而，通过功能性吸收坑实验，我们发现在TRPV5（-/-）小鼠的破骨细胞培养物中几乎没有骨吸收，这支持了在体内观察到的骨吸收受损。综上所述，TRIPV5缺乏导致破骨细胞大小和数量增加，Ca2+吸收无功能。本报告确定TRPV5是一个上皮Ca2+通道，对破骨细胞骨吸收至关重要，并证明了跨细胞Ca2+运输在破骨细胞功能中的重要性。
Bone remodeling involves the interplay of bone resorption and formation and is accurately controlled to maintain bone mass. Both processes require transcellular Ca2+ transport, but the molecular mechanisms engaged remain largely elusive. The epithelial Ca2+ channel TRIPV5 is one of the most Ca2+-selective transient receptor potential (TRP) channels. In this study, the functional role of TRPV5 in bone was investigated. TRPV5 mRNA was expressed in human and murine bone samples and in osteoclasts along with other genes involved in transcellular Ca2+ transport, including calbinclin-D-9K and calbindin-D-28K, Na+/Ca2+ exchanger 1, and plasma membrane Ca2+-ATPase 1b. TRPV5 expression in murine osteoclasts was confirmed by immunostaining and showed predominant localization to the ruffled border membrane. However, TRPV5 was absent in osteoblasts. Analyses of femoral bone sections from TRPV5 knockout (TRPV5(-/-)) mice revealed increased osteoclast numbers and osteoclast area, whereas the urinary bone resorption marker deoxypyridinoline was reduced compared with WT (TRPV5(+/+)) mice. In an in vitro bone marrow culture system, the amount of osteoclasts and number of nuclei per osteoclast were significantly elevated in TRPV5(-/-) compared with TRPV5(+/+) mice. However, using a functional resorption pit assay, we found that bone resorption was nearly absent in osteoclast cultures from TRPV5(-/-) mice, supporting the impaired resorption observed in vivo. In conclusion, TRIPV5 deficiency leads to an increase in osteoclast size and number, in which Ca2+ resorption is nonfunctional. This report identifies TRPV5 as an epithelial Ca2+ channel that is essential for osteoclastic bone resorption and demonstrates the significance of transcellular Ca2+ transport in osteoclastic function.