Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd
Lrp6 hypomorphic mutation affects bone mass through bone resorption in mice and impairs interaction with Mesd
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DOI：
10.1359/jbmr.080512
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发表时间：
2008-10-01
影响因子：
6.2
通讯作者：
Ozono, Keiichi
中科院分区：
文献类型：
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作者：
Kubota, Takuo;Michigami, Toshimi;Ozono, Keiichi
低密度脂蛋白受体相关蛋白5（LRP 5）通过控制骨形成来调节骨获得。由于LRP 6，另一个辅助受体，在出生后骨代谢的作用还没有完全阐明，我们研究了骨表型在小鼠窝藏所有LRP 6亚型突变，ringelschwanz（rs）。并对突变蛋白进行了表征。先我们进行了pQCT，骨组织形态计量学。和Lrp 6（rs/rs）和Lrp 6（+/+）小鼠的胫骨油的免疫组织化学和测定骨转换的生化参数。Lrp 6（rs/rs）小鼠在pQCT中表现出减少的小梁BMD。骨组织形态计量学显示骨体积减少和骨小梁数量减少，这与侵蚀表面增加有关。尿脱氧吡啶啉排泄增加Lrp 6（rs/rs）小鼠，而血清骨钙素水平Lrp 6（rs/rs）小鼠和野生型同窝出生。在Lrp 6（rs/rs）成骨细胞中，头盖骨来源的成骨细胞的细胞数量和矿化的增加没有受损。在体内和体外Lrp 6（rs/rs）成骨细胞中Rankl表达增加，并且在Lrp 6（rs/rs）细胞中体外破骨细胞生成和骨吸收活性加速。用canonical Writ处理抑制了原代成骨细胞和ST 2细胞中的Rankl表达。Lrp 6的过表达也抑制Rankl表达。而Lrp 6 rs突变蛋白则没有。Lrp 6 rs突变体的功能分析显示，由于与中胚层发育（Mesd）（Lrp 6的伴侣蛋白）的相互作用减少，导致Wnt/β-连环蛋白信号转导受损，因此对质膜的靶向降低。这些结果表明，Lrp 6介导的信号控制出生后的骨量，至少部分通过调节骨吸收。还表明与Mesd的相互作用对于Lrp 6发挥功能至关重要。
Low-density lipoprotein receptor-related protein 5 (LRP5) regulates bone acquisition by controlling bone formation. Because roles of LRP6, another co-receptor for Writs, in postnatal bone metabolism have not been fully elucidated, we studied bone phenotype in mice harboring all Lrp6 hypomorphic mutation, ringelschwanz (rs). and characterized the mutant protein. First. we performed pQCT, bone histomorphometry. and immunohistochemistry oil tibias of Lrp6(rs/rs) and Lrp6(+/+) mice and determined biochemical parameters for hone turnover. Lrp6(rs/rs) mice exhibited reduced trabecular BMD in pQCT. Bone histomorphometry showed low boric Volume and decreased trabecular number, which were associated with increased eroded surface. Urinary deoxypyridinoline excretion was increased in Lrp6(rs/rs) mice, whereas levels of serum osteocalcin were comparable between Lrp6(rs/rs) mice and wildtype littermates. Increase in cell number and mineralization of calvariae-derived osteoblasts were not impaired in Lrp6(rs/rs) osteoblasts. Rankl expression was increased in Lrp6(rs/rs) osteoblasts both in vivo and in vitro, and osteoclastogenesis and bone-resorbing activity In vitro were accelerated in Lrp6(rs/rs) cells. Treatment with canonical Writ suppressed Rankl expression in both in primary osteoblasts and ST2 cells. Overexpression of Lrp6 also suppressed Rankl expression. whereas the Lrp6 rs mutant protein did not. Functional analyses of the Lrp6 rs mutant showed decreased targeting to plasma membrane because of reduced Interaction with Mesoderm development (Mesd), a chaperone for Lrp6, leading to impaired Wnt/beta-catenin signaling. These results indicate that Lrp6-mediated signaling controls postnatal bone mass, at least partly through the regulation of bone resorption. It is also suggested that the interaction with Mesd is critical for Lrp6 to function.